contents chapter 09 - University of Groningen · and erythropoietin [335], amongst others, which...

contents

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chapter09

endothelial progenitor cell-based

neovascularization:

implications for therapy

Guido Krenning, Marja JA van Luyn1 and Martin C Harmsen1

Stem Cell & Tissue Engineering Research Group, Dept. Pathology & Medical Biology, University Medical Center Groningen, University of Groningen, The Netherlands

Trends in Molecular Medicine 2009; In press

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chapter 9 endothelial progenitor cell-based neovascularization

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abstract

Ischemic cardiovascular events are the major cause of death globally. Endothelial progenitor cell (EPC)-based therapies result in improvement of vascular perfusion and may offer clinical benefit. However, discrepancy between functional improvement and the paucity of long-term EPC engraftment raises controversy on their mechanism-of-action. We and others hypothesized that following ischemic injury, EPC induce neovascularization through the secretion of cytokines and growth factors which act in paracrine fashion and induce sprouting angiogenesis by the surrounding endothelium. In this concise review, we address the (patho)physiology of EPC-induced neovascularization and focus on the paracrine signals secreted by EPC and the effects they elicit. In future therapy, clinical administration of these paracrine modulators using slow-release depots may induce neovascularization and holds promise for vascular regenerative medicine.

ischemic cardiovascular disease and neovascularization

Cardiovascular pathologies, such as myocardial infarction and ischemic diseases, are the number one cause of death globally. In 2005, an estimated 17.5 million people died from cardiovascular diseases, representing approximately 30% of all global deaths (www.who.org). Vascular occlusions, resulting in tissue ischemia, are the main cause of cardiovascular events such as myocardial infarction. Hence, current standard treatments focus on the relief of ischemia, predominantly by restoring vascular perfusion in order to prevent ongoing tissue damage, but fail to induce tissue regeneration. Therefore, the search for new therapies that induce tissue regeneration is warranted, although also these therapies do not abolish the underlying causes of cardiovascular disease.

Immediately after ischemic damage, such as myocardial infarction, a local inflammatory response is mounted which is important for the clearance of cell debris and to form the scar that preserves tissue integrity [269;270]. Tissue perfusion plays an important role during this inflammatory reaction and scar formation [303;304]. Preservation of the vasculature, or even induction of vascularization in the ischemic region may decrease the lesion size, prevent loss of cells through apoptosis [305] and eventually may inhibit the development of organ failure [306]. Hence, (progenitor) cell therapy for the induction of neovascularization is currently assessed in clinical trials (Table 1).

Adult neovascularization, or the de novo formation of blood vessels, is classically regarded to be a consequence of angiogenesis, rather than vasculogenesis. Angiogenesis, the process whereby new blood vessels are formed from pre-existing vessels (reviewed in [307;308]). Sprouting angiogenesis encompasses an increase of vasopermeability, leading to extravagation of plasma proteins that function as temporal scaffold for migrating endothelial cells (EC). Matrix metalloproteases, secreted by the endothelium, break down the vascular basement membrane and allows migration of EC. Proliferation and subsequent migration of newly-formed EC results in the formation of a solid endothelial cord. Lumen formation and stabilization are the final processes of sprouting angiogenesis (Figure 1A).

Vasculogenesis, the generation of new blood vessels by stem/progenitor cells (Figure 1B), was long-time regarded to be confined to embryogenesis. However the discovery of endothelial progenitor cells (EPC) in adult bone marrow and peripheral blood has challenged this theory [46]. Endothelial progenitor cells contribute to repair of vascular damage in vivo [61;309].

Physiological, EPC-induced neovascularization is initiated by hypoxia. In short, EPC-driven neovascularization starts with mobilization of EPC from the bone marrow to the circulation in response to stress- and/or damage signals, e.g. VEGF, SDF-1 and MCP-1 [310;311], migration of EPC through the blood stream and extravasation of EPC through the endothelium and migration towards the site of neovascularization where they contribute to the formation of the neovessels. Since EPC contribute to adult neovascularization, these progenitor cells make appropriate candidates as cell therapeutic for the treatment of various ischemic diseases. Herein, EPC are isolated from the peripheral blood and implanted into the ischemic tissue where they are involved in restoration of vascular perfusion (reviewed in [312]). However, controversy exists on the mechanism by which human EPC induce neovascularization in such a

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regenerative medicine for they are involved in vascular homeostasis and repair [99], neovascularization [70;71] and in various cardiovascular diseases [313;314].

Although there is controversy on the phenotype of EPC and EPC subtypes (reviewed in [312] and [170]), in general, two types of EPC can be discriminated based on their surface antigen expression, proliferation potential and time of emergence in cell culture [62]. Commonly, these EPC emerge from peripheral blood MNC, typically adhere to gelatin and fibronectin, take up acetylated LDL, bind lectins from Ulex europaeus, and express marker proteins of the EC lineage, e.g. CD31, CD144 (VE-Cadherin) von Willebrand Factor (vWF) and endothelial cell Nitric Oxide Synthase (eNOS), after cell culture [315;316].

‘Early outgrowth EPC’ [62], also known as ‘colony forming unit-EC’ [63], ‘endothelial-like cell’ [101] or ‘CD14+ EPC’ [113], are derived from the monocytic (CD14+) cell lineage (Figure 2A) and form clusters from which cells with a spindle-shaped morphology originate as early as 7 days of culture. CD14+ EPC possess transient proliferative potential in vitro [101;113], cannot be passaged and display overlap between endothelial- and monocyte/macrophage cell markers and functions, i.e. phagocytosis [63;196], antithrombogenic activity [113;197], and the production of vasoactive substances [113;317].

‘Late outgrowth EPC’, also known as ‘endothelial colony forming cells’ [47;63] or ‘CD34+ EPC’ [100;268], are thought to originate from the CD34+ hematopoietic stem cell (Figure 2B) [47;63] and exclusively expresses markers of the endothelial cell lineage after cell culture. CD34+ EPC emerge after 14-28 days in culture as colonies

therapeutic setting. Hence, this concise review further focuses on the mechanisms of human EPC-induced neovascularization; in particular their pro-angiogenic effects, and offers new therapeutic approaches to induce neovascularization therapeutically.

endothelial progenitor cells, cell therapies and current (clinical) outcome

Adult EPC were first described by Asahara et al. [46]. In their landmark paper, the differentiation of cells bearing EC markers from peripheral blood mononuclear cells (MNC) enriched for expression of glycoprotein CD34 or vascular endothelial growth factor receptor-2 (VEGFR-2) was described. These EPC contributed to revascularization and the salvage of ischemic hind limbs [46]. Ever since, EPC are at the center of

A. Sprouting Angiogenesis B. Vasculogenesis

1

2

3

4

5

1

2

3

4

Figure 1. Mechanisms of angiogenesis (A) and vasculogenesis (B). Sprouting angiogenesis encompasses the secretion of matrix metalloproteases that break down the vascular basement (A2) membrane and allows migration of EC (A3). Proliferation and subsequent migration of newly-formed EC results in the formation of a solid endothelial cord (A4). Lumen formation and stabilization are the final processes of sprouting angiogenesis (A5). Vasculogenesisbegins with the formation of a primary vascular plexus by EPC (B2). Matrix deposition (B3) and lumen formation (B4) by EPC result in the formation of immature capillaries.

Hematopoietic stem cell

Macrophage

Mature endothelial cell

CD34+

CD34+, CD133-, VEGFR-2+, CD14+/-, CD1a-, CD45-, CD31+,

CD144+, vWF+, eNOS+, Tie2+

CD14+, CD1a+, CD45+,CD68+, CD163+

ematopoietic stem ce

CD34+

Hematopoietic Cells* Red Blood Cells* Lymphoid Cells* Granulocytes* etc.

M h

C +,CD68+, CD163+

Macrophage

CD14+, CD1a+, CD45+

Mature endothelial cell

CD34 +,CD14+/-, CD1a-, CD45-, CD31+,

4+, CD133-, VEGFR-2++/ CD1 CD45 CD3

ature endothelial cell

Hemangioblast

CD34+, CD133+,VEGF-R2+

Hemangioblast

CD133 ,VEGF R2CD34+,

133+,VEGF-R2+

Myeloid Progenitor cell

CD14+, CD45+

yeloid Progenitor cell

C

oid Progenitor ce

CD14+, CD45+

Monocyte

CD14+, CD1a+, CD45+,CD68-, CD163-

Monocyte

D14 +,CD68 , CD163

Monocyte

4+, CD1a+, CD45+CD68- CD163-

Early outgrowth Endothelial Progeitor Cell

CD14+, CD1a+, CD45+,CD31+, VEGFR-2+, CD144-,

vWF-, eNOS-, Tie2-

Early outgrowth Endothelial Progeitor Cell

C +,CD31+, VEGFR-2+, CD144-,

ndothelial Progeitor C

CD14+, CD1a+, CD45++ +

Late OutgrowthEndothelial Progenitor Cell

CD34+, CD133+, VEGFR-2+,CD31+, CD144-, vWF-, eNOS-, Tie2-

gEndothelial Progenitor Cell

CD R-2+,1+, CD144-, vWF-, eNOS-, Tie

dothelial Progenitor C

D34+, CD133+, VEGFR+ CD144 WF NO

Figure 2. Origin and fate of endothelial progenitor cells. CD14+ EPC originate from the myeloid cell lineage and coexpress marker proteins from the myeloid- and endothelial cell lineage. CD34+ progenitor cells originate directly from the hemotopoietic stem cell and exclusively express markers from the endothelial cell lineage.

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proteins, such as VEGF [329;330], SDF-1 [331;332], MCP-1) [333], angiopoietins [334] and erythropoietin [335], amongst others, which actively recruit both CD14+ EPC and CD34+ EPC from the bone marrow into the circulation, towards the site of hypoxia (Figure 3A).

vascular permeability, extravasation and tunneling by cd14+ epc.

Vascular permeability increases as a response to hypoxia-induced factors, especially VEGF and MCP-1 (reviewed in [336]). Increased VEGF signaling, through its receptor

of cobblestone-appearance that resemble microvascular EC and display an almost indefinite proliferation potential [47;318]. In contrast to CD14+ EPC, CD34+ EPC do not exhibit functional overlap with cells of other lineages.

Although CD14+- and CD34+ EPC come from distinct origins and behave functionally different in vitro, both CD14+ EPC and CD34+ EPC contribute to in vivo neovascularization in several disease models [319-321], albeit their mechanism-of-action remains controversial.

Phase I and II clinical trials have aimed to restore blood flow to the ischemic areas using various subsets of EPC (Table 1). Placebo-controlled trials studying acute myocardial infarction and chronic ischemic heart disease represent the majority of current clinical trials (Table 1; reviewed in [312] and [322]) Although controversy exists on the recovery of ventricular function [323], implantation of any given EPC-type was reported to increase ventricular ejection fraction, reduce the infarct size, and improve myocardial perfusion in the majority of trials. Of particular interest, patients receiving EPC implantation concomitantly showed a reduction of cardiovascular symptoms and increased exercise capacity [324;325].

Although a clear beneficial effect of EPC implantation is observed is clinical trials, recent results in animal studies raise controversy on their mechanism of action [65] (Table 1). The original hypothesis that EPC would differentiate into EC that subsequently build up the neovasculature [200;296], is challenged by recent observations that implanted EPC can be traced only shortly after implantation and do not associate with the neovasculature [262;274]. Accordingly, we and others hypothesized that EPC induce therapeutic neovascularization though paracrine signaling, i.e. the secretion of pro-angiogenic factors [100;274]. Therefore, the next part of this review will focus on the physiological role of EPC after ischemic injury and the paracrine signals they exert during neovascularization in vivo.

physiological neovascularization by endothelial progenitor cells

relies on paracrine signaling events

endothelial progenitor cells and response to injury.

Obstruction of peripheral or coronary arteries, either acutely or chronically, reduces blood blow and as a consequence the delivery of oxygen and nutrients. The natural response of the tissue in states of hypoxia is to increase production and secretion of factors that stimulate inflammation and neovascularization in order to alleviate the hypoxia [326].

Of particular interest herein is the family of hypoxia-inducible transcription factors (HIF) and its primary member HIF-1. HIF-1 is a heterodimeric transcription factor composed of two subunits HIF-1α and HIF-1β that are constitutively expressed in most cell types [327]. In a normoxic environment, HIF-1α protein levels decay rapidly through ubiquitin-proteasome degradation [328]. However, in a hypoxic environment HIF-1α protein is stabilized and induces the transcription of multiple pro-angiogenic

Table 1. Clinical trials and animal models for EPC-based therapy during cardiovascular disease

Disease (Model) Cell Source Delivery Site OutcomeEPC engraftment

in vasculature?

Myocardial InfarctionAhmadi et al. [374]

BOOST trials [375;376]HEBE [377;378]

REPAIR-AMI [379;380]TOPCARE-AMI [298;381]

Intractable AnginaLosordo et al. [297]

Critical Limb IschemiaTateishi-Yuyama et al. [382]

Van Huyen et al. [383]

Zhang et al. [384]

Animal models for human diseaseMyocardial InfarctionBotta et al. [200]

Jackson et al. [266]

Ma et al. [267]

Ott et al. [385]

Sondergaard et al. [386]Urbrich et al. [368]

Critical Limb IschemiaAsahara et al. [46]Koponen et al. [387]

Ziegelhoeffer et al. [274]

CD133+ EPC

Unselected BMCUnselected BMC

CD14+ EPC & CD34+ EPC

CD14+ EPC

CD34+ EPC

Unselected BMC

Unselected BMC

Unselected BMC

CD34+ EPC

CD34lowcKIT+Sca1+ EPC

Unselected UCBC

Cultured CD34+ EPC

CD34+ EPCCD14+ EPC

CD34+ EPCCD34+ EPC

Unselected BMC

Intramyocardial

IntracoronaryIntracoronary

IntracoronaryIntracoronary

Intramyocardial

Intramuscular

IntramuscularI

ntramuscular

Intramyocardial

Intravenous

Intravenous

Intramyocardial

IntramyocardialIntramuscular

IntramuscularIntramuscular

Bone marrow trasplant

Effective: ↓ WMSI, ↑ myocardial viability, ↑ myocardial perfusion

at 6 monthsIneffective at 18 months

Effective: ↑ LVEF, ↓ Infarct size at 4 months

Effective: ↑ LVEF, ↑ CBF at 12 monthsEffective: ↑ LVEF, ↓ LEV at 12 months

Inconclusive

Effective: ↑ Exercise ability, ↑ ABI, ↓ rest pain at 6 months

Effective: ↑ tissue perfusion at 6 months

Effective: ↑ tissue perfusion, ↑ capillary density, ↑ ABI, ↓ rest pain,

↑ exercise ability at 1 month

Effecrive: ↑ LVEF, ↓ infarct size, ↑ myocardial perfusion

Effective: ↑ myocardial viability, ↑ myocardial perfusion

Effective: ↓ infarct size, ↑ myocardial perfusion

Effecrive: ↑ LVEF, ↓ infarct size, ↑ myocardial perfusion

IneffectiveUnknown

Effecrive: ↑ Limb perfusionEffecrive: ↑ Limb perfusion,

↓ necrotic areaEffective: ↑ Limb perfusion

Unknown

UnknownUnknown

UnknownUnknown

Unknown

Unknown

Inconclusive

Unknown

Unknown

3.3%

Yes, limited

Yes, high

NoneYes, limited

Yes, highNone

None

ABI = Ankle-brachial index; AMI = Acute myocardial infarction; BMC = bone marrow cells; CBF = coronary blood flow; CHD = Coronary heart disease; LVEF = Left ventricular ejection fraction; LEV = Late enhancement volume; WMSI = Wall motion score index;

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VEGFR-2, increases vascular permeability by destroying the endothelial adherens junctions. Herein, VEGF/VEGFR-2-dependent phosphorylation of VE-Cadherin results in its internalization [337], thus decreasing the endothelial cell-cell contacts. MCP-1 signaling through its receptor CCR2, amplifies this VEGF-dependent increase in permeability. MCP-1/CCR2 signaling in EC results in downstream phosphorylation and degradation of claudins and occludins, the major constituents of tight junctions [338;339]. Hence, the vascular permeability is further increased, facilitating progenitor cell extravasation (Figure 3B).

Extravasation of progenitor cells is orchestrated by cell-cell adhesion between the progenitor cells, chemotactic gradients, and vascular permeability. In response to pro-inflammatory stimuli, released from hypoxic tissues (e.g. IL-1β, IL-8 and MCP-1), EC increase expression of cell-cell adhesion molecules, such as E-selectin, ICAM-1, VCAM-1 and the β1-integrins [340]. Circulating CD14+ EPC initiate weak cell-cell interactions with the endothelium, which induces an increase in expression these similar adhesion molecules by the CD14+ EPC [341;342]. Increased expression of adhesion molecules facilitates the formation of firm cell-cell adhesions between CD14+ EPC and the endothelium, hence initiating the multi-step process of adhesion and transendothelial migration (Figure 3B).

After transendothelial migration, progenitor cells encounter the endothelial basement membrane and the extracellular matrix (ECM). CD14+ EPC secrete matrix metalloproteinases (MMP) and matrix metalloelastases (MME), which locally degrade the endothelial basement membrane and ECM [281]. Of particular interest, matrix degradation and migration of CD14+ EPC towards sites of hypoxia puts down a network of tunnels that may act as template for capillary formation (Figure 3C). Using transgenic mice that express β-galactosidase under the control of the endothelium-specific Tie-2 promoter, Moldovan and coworkers showed that CD14+ EPC drilled tunnels in the ischemic myocardium in a MCP-1-dependent manner [271;281]. Furthermore, the authors showed that tunneling by CD14+ EPC was achieved through asymmetrical degradation of the ECM following secretion of MMP-12 or MME [281]. The branched tunnels contained erythrocytes, indicating functional coupling to the vasculature, but were devoid of the commonly used endothelial marker Tie-2. However, the absence of clotting suggests that the CD14+ EPC lining the capillary-like tunnels did assume the morphological appearance of the endothelium and endothelial functionalities such as antithrombogenicity. These characteristics are in line with the (early) CD14+ EPC phenotype, which is reported by us and others to exert antithrombogenic behavior, but does not express all common EC markers [62;113;197]. In a later phase of neovascularization, these CD14+ EPC are replaced by either CD34+ EPC or mature EC, as is described below. The CD14+ EPC however act as ‘architects of vessel development’ assisting in neovascularization of ischemic tissues. Corroboratory, depletion of CD14+ cells from the peripheral blood did decreases neovascularization in a mouse model for myocardial infarction [270].

recruitment of cd34+ epc.

Another interesting postulation by Anghelina et al. is that the CD14+ EPC-derived tunnels are subsequently colocalized by Tie-2+ bone marrow-derived progenitor

* HIF-1 Stabilization* Secretion of Pro-Angiogenic Factors* Recruitment of CD14+ EPC

pO2 pO2pO2 pO2

VEGFa, MCP-1, IL-8, SDF-1, ANGPT-1

HYPOXIA

* Disruption of Endothelial Cell-Cell Adhesions* Increased Vascular Permeability* Extravasation of EPC

* Degration of Endothelial Basement Membrane* Drilling of Pre-Capillary tunnels

* Creation of a Pro-Angiogenic Microenvironment* Sprouting Angiogenesis into Capillary-like tunnels

A

B

C

D

Endothelial Cell Endothelial Progenitor Cell White Blood Cellol Cellell ndoEnndonEnEn l PProgenitoii WWellr CeCCellCeC llCC lll

Figure 3. Mechanisms of physiological neovascularization. (A) Hypoxia induces the secretion of pro-angiogenic factors that mobilization of EPC in the bone marrow and recruits them to the site of hypoxia. (B) Recruited EPC adhere to the endothelium and start transendothelial migration. (C) Degradation of the endothelial basement membrane and tunneling of CD14+ EPC creates a (temporal) capillary-like scaffold for the neovasculature. (D) Paracrine signaling by CD14+ EPC and CD34+ EPC results in the production of an angiogenic microenvironment that stimulates the nearby endothelium to proliferate and cover the capillary-like tunnel walls. Subsequent sprouting angiogenesis efficiently transforms the capillary-like tunnels into functional and mature capillaries.

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Taken together, physiologic neovascularization results from interplay between the mature endothelium and EPC. Herein, two distinct EPC-types can be distinguished, the CD34+ EPC and the CD14+ EPC, with distinct and overlapping functions. The CD14+ EPC tunnels towards the site of hypoxia, generating a template for capillary formation. Furthermore, through the secretion of pro-angiogenic factors, these CD14+- and CD34+ EPC generate a pro-angiogenic environment. The preexisting endothelium reacts by sprouting angiogenesis and ensures the conversion of capillary-like tunnels into mature capillaries using the capillary-like tunnels as a neovascularization template (Figure 3).

Although both EPC and the preexisting endothelium add to neovascularization, controversy remains on their relative contribution to neovascularization in various disease states. This issue has to be elucidated prior to large-scale application of EPC-based cardiovascular therapies.

towards clinical application

The biology of EPC is complex and currently deserves further dissection. However, considering that EPC were discovered only a mere decade ago, huge progress has been made in understanding the significance of phenotypic variations in progenitor cell types (reviewed in [312] and [170]) and to use them to our advantage for vascular regenerative medicine (reviewed in [346]). Popa et al., among others, described that the engraftment of bone marrow-derived EPC in neovascularization is determined by the local microenvironment [169]. Hence, incorporation of EPC into the neovasculature can be found in one setting, while in other cases no such contribution is found [63;343]. However, the EPC may interpret these molecular clues and is able to change that same microenvironment for the better. For one, the secretion of pro-angiogenic factors by EPC can induce sprouting angiogenesis and thus improve tissue perfusion after ischemic injury. Also, EPC literally pave the way for vessel development by drilling tunnels in damaged tissues which later develop into the neovasculature.

As in most biological processes, EPC are influenced by a plethora of systemic and local factors, which influence experimental outcome. Understanding these processes therefore opens new possibilities for therapeutic intervention and will continue to be the focus of future research. Current insight in the mechanism of EPC-induced neovascularization, for instance its dependence on VEGF, has led to the use of VEGF gene therapy in clinical trials [347] and the development of protein-release systems for the delivery of growth factors [348]. Similarly, in cancer therapies, insights in the process of neovascularization have led to the development and use of neutralizing antibodies to the paracrine mediators of neovascularization [349].

Obviously, mimicking the natural release of pro-angiogenic molecules by EPC is difficult to achieve using conventional drug-delivery systems, which generally show burst-release. In contrast to burst-release, dosing and timing of pro-angiogenic factors is of major importance during neovascularization. Therefore, a huge research effort has been undertaken in order to mimic these release patterns in vascular regenerative medicine. It is likely that the optimal treatment will involve multiple agents as neovascularization is a complex process involving a large variety of factors.

cells [282], which phenotypically represent the CD34+ EPC. We therefore postulate that these bone marrow-derived Tie-2+ progenitors are CD34+ EPC. The capillary-like tunnels, formed by CD14+ EPC, undergo a process of complex cellular organization that comprises robust vasculogenesis [271;282]. CD34+ EPC are actively recruited to the capillary-like tunnels and these immature EC replaced the CD14+ EPC cells lining the lumen. Although Anghelina et al. provided firm evidence for colonization of the capillary-like tunnels by EPC [271;282], the underlying mechanisms remain to be elucidated. Secretion of chemokines by CD14+ EPC, such as IL-8, GM-CSF, HGF, SDF-1 or SCF, may be an important determinant for CD34+ EPC recruitment and has been described previously [64;73]. Furthermore, the conversion of capillary-like tunnels formed by CD14+ EPC into capillaries lined by CD34+ EPC explains the transient existence of CD14+ EPC-derived capillaries and may account for the wide-spread idea that solely CD34+ EPC engraft into the neovasculature [62;63;343].

production of a pro-angiogenic niche and induction of endothelialization and sprouting angiogenesis.

CD14+ EPC and CD34+ EPC secrete high amounts of proangiogenic cytokines under hypoxic conditions. Of note, several research groups have described the secretion of proangiogenic factors HGF, IGF-1, bFGF and VEGF by both EPC-types [64;276;344]. Moreover, interaction between CD34+ EPC and CD14+ EPC has been described to differentially and synergistically increase the secretion of these proangiogenic mediators by several research groups [64;113;202]. We therefore contemplated that, during neovascularization, interaction between the CD14+ EPC and the CD34+ EPC in the capillary-like tunnels results in the formation of a proangiogenic niche which favors the conversion the capillary-like tunnels into mature and functional capillaries.

Sprouting angiogenesis can be initiated by EPC and is currently believed to be the major contributor to the neovasculature [65;274]. In response to the proangiogenic stimuli secreted by either CD34+ EPC or CD14+ EPC, the surrounding endothelium starts to proliferate and invade the capillary-like tunnels (Figure 3D). In corroboration, conditioned media from EPC cultures was shown to induce proliferation and migration of EC both in vitro as well as in vivo [330;345].

As previously mentioned, the differentiation of EPC into mature and functional EC may also contribute to the conversion of the capillary-like tunnels into functional capillaries. We have recently shown that endothelial cell differentiation by CD14+ EPC increased after exposure to HGF produced by CD34+ EPC [113]. Furthermore, Yoon and coworkers and Awad and coworkers reported increased endothelial differentiation and increased neovascularization after combined administration of CD34+ and CD14+ EPC into ischemic hind limbs [64;202]. Although synergism between CD34+ EPC and CD14+ EPC increases endothelial cell differentiation in vitro and neovascularization in vivo, the number of chimeric EPC/host-vessels remains low (Krenning & Harmsen, unpublished data) [64;202], suggestive of a major contribution from the surrounding endothelium through sprouting angiogenesis.

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Another potential difficulty is the status of the affected endothelium in the ischemic region. Compromised endothelium will not migrate nor proliferate as well as healthy endothelium, therefore potentially limiting the extent of neovascularization induced by such therapies. These impairments pose new challenges for vascular regenerative medicine and strategies to overcome these impairments need to be addressed in future research.

Lastly, the ischemic microenvironments may differ between tissues and organs. Therefore, standardized protein-based therapy for the induction of neovascularization may not be the most promising option, and future research will have to elucidate the molecular microenvironment of each ischemic disease in order to achieve the most suitable treatment. Even more so, it is most likely that each individual patient will behave differently to ischemic damage and minor adjustments to the protein-based therapies will have to be made in order to achieve the highest clinical benefit. This form of personalized medicine, although in future perspective, will in our opinion ensure the best regenerative therapy.

concluding remarks

Neovascularization by EPC is a complex process that is initiated by local hypoxia, modulated by EPC, and results in the de novo formation of blood vessels. In this concise review we have shown that administration of EPC, either systemically or locally into ischemic tissues, results in increased vascular perfusion and clinical benefit (Table 1) not by incorporation into the neovasculature, but by drilling capillary-like tunnels and stimulating sprouting angiogenesis through paracrine signals (Figure 3). First, EPC are actively recruited to sites of neovascularization where they form capillary-like tunnels mimicking robust vasculogenesis. Second, the frequency of chimeric human/mouse blood vessels is too low to explain the significant increase in vascular perfusion. Third, human EPC secrete a plethora of factors which act as chemoattractants and mitogens on surrounding endothelial cells. Four, sprouting angiogenesis by the host endothelium is always observed after EPC-induced neovascularization in animal models of ischemic disease.

The demonstration that human EPC secrete paracrine signals that induce neovascularization offers great therapeutic potential. For one, protein-based therapies may be more easily translated into a clinical setting. In this respect, knowledge on EPC-mediated neovascularization has led to the development of biologicals which influence or mimic the soluble mediators of neovascularization (e.g. VEGFa and bFGF), and clinical administration of such pro-angiogenic factors has shown promising results. However, the beneficial paracrine signals secreted by EPC remain partly unidentified.

The development of ‘on-demand release’ depots, containing multiple pro-angiogenic factors that are secreted in temporal distinct or cell-dependent patterns will mimic paracrine signaling events during neovascularization more closely, however the development of such release depots is still in its early days and the clinical efficacy of such protein-based therapies need to be elucidated in clinical trials. However, if these hurdles can be overcome, protein-based therapy will hold great promise for vascular regenerative medicine.

Administration of a single factor may therefore be insufficient. Current investigations on growth factor delivery platforms focus on the sequential delivery of multiple pro-angiogenic factors, mimicking the in vivo behavior of EPC. For example, Hao et al. have described the sequential release of VEGF and PDGF-BB in a mouse model of myocardial infarction and described increased vascularization and improved vessel maturation compared to either factor alone [350]. Likewise, we have recently supplemented Matrigel implants with not just a duplet, but a pentet of growth factors and cytokines (Krenning & Harmsen, unpublished data). This pentet of factors, containing the chemokines MCP-1, IL-8 and growth factors HGF, bFGF and VEGF, was able to induce neovascularization at a level comparable to neovascularization induced by EPC.

Since therapeutic neovascularization can be induced by the administration of a multiplex of growth factors and cytokines, this protein-based therapy offers a great potential for therapeutic application. New classes of biomaterials with slow-release capability may be created to house these pro-angiogenic factors. Hence, such materials will offer an ‘off-the-shelf’ therapeutic for the induction of neovascularization by the recruitment of EPC or by inducing sprouting angiogenesis from the endothelium nearby.

However, these materials would have to incorporate some form of biological responsiveness to their environment, since previous attempts to induce neovascularization through burst release of growth factors or gene therapy also caused serious complications as blood vessel overgrowth, i.e. hemagiomas [58].

A highly interesting development is the generation of ‘release-on-demand’ platforms that use the principles of enzyme-mediated growth factor release. Physiologically, growth factors are stored in the extracellular matrix from which they are released by degrading enzymes secreted from invading or growing cells [351]. This enzyme-mediated release guarantees a time and location restricted action of these growth factors. For therapeutic neovascularization, it was shown that only the proper and timely delivery of vessel-inducing factors (i.e. VEGF and bFGF) and blood vessel maturating factors (i.e. PDGF and TGF-β) were able to form functionally mature vessels of EC and smooth muscle cells in vivo [352]. Obviously, mimicking such complicated series of events is challenging, but several release systems have been successfully established [258;259;353].

A potential difficulty in the clinical success of growth factor-delivery systems is the availability and functionality of the EPC. In this review we have illustrated the function of EPC in orchestrating neovascularization and the potential of growth factor-delivery for vascular regenerative medicine. However, the numbers and function of these EPC may be affected as a result of the disease. We and others have described functional impairment of EPC in various diseases, including inflammatory diseases [108], renal diseases [354] and cardiovascular diseases [261]. Corroboratory, Kränkel and coworkers recently described decreased migratory activity of EPC from patients with cardiovascular disease [355]. However, in their experiments the cells that did migrate showed no reduction in their angiogenic capacity. These data suggest that although there is a numerical dysfunction of EPC in patients with cardiovascular diseases, there are remaining EPC with proper angiogenic function. Hence, mobilization of these EPC by statin treatment may overcome current limitation observed in EPC-mediated therapy. However, this remains to be elucidated in future research.

appendices

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references

207 App

references

vaartjes i, peters rjg, van dis s, bots m. hart- en vaatziekten in nederland. in: vaartjes i, peters rjg, van dis s, bots m, editors. hart- 1.

en vaatziekten in nederland, najaar 2006 - cijfers over ziekte en sterfte. den haag: nederlandse hartstichting, 2006. p. 9-18.

eefting f, rensing b, wigman j, pannekoek wj, liu wm, cramer mj, lips dj, doevendans pa. role of apoptosis in reperfusion injury. 2.

cardiovasc res 2004; 61: 414-426.

boyle em, jr., pohlman th, johnson mc, verrier ed. endothelial cell injury in cardiovascular surgery: the systemic inflammatory 3.

response. ann thorac surg 1997; 63: 277-284.

costa c, soares r, schmitt f. angiogenesis: now and then. apmis 2004; 112: 402-412.4.

carmeliet p. mechanisms of angiogenesis and arteriogenesis. nat med 2000; 6: 389-395.5.

harkness ml, harkness rd, mcdonald da. the collagen and elastin content of the arterial wall. j physiol 1955; 127: 33-4p.6.

deyl z, jelinek j, macek k, chaldakov g, vankov vn. collagen and elastin synthesis in the aorta of spontaneously hypertensive rats. 7.

blood vessels 1987; 24: 313-320.

gudiene d, valanciute a, velavicius j. collagen network changes in basilar artery in aging. medicina (kaunas) 2007; 43: 964-970.8.

jenkins c, milsted a, doane k, meszaros g, toot j, ely d. a cell culture model using rat coronary artery adventitial fibroblasts to 9.

measure collagen production. bmc cardiovasc disord 2007; 7: 13.

walker-caprioglio hm, trotter ja, mercure j, little sa, mcguffee lj. organization of rat mesenteric artery after removal of cells of 10.

extracellular matrix components. cell tissue res 1991; 264: 63-77.

frid mg, shekhonin bv, koteliansky ve, glukhova ma. phenotypic changes of human smooth muscle cells during development: late 11.

expression of heavy caldesmon and calponin. dev biol 1992; 153: 185-193.

bennett mr, farnell l, gibson wg. a Quantitative description of the contraction of blood vessels following the release of 12.

noradrenaline from sympathetic varicosities. j theor biol 2005; 234: 107-122.

poliseno l, cecchettini a, mariani l, evangelista m, ricci f, giorgi f, citti l, rainaldi g. resting smooth muscle cells as a model for 13.

studying vascular cell activation. tissue cell 2006; 38: 111-120.

matsuki t, hynes mr, duling br. comparison of conduit vessel and resistance vessel reactivity: influence of intimal permeability. 14.

am j physiol 1993; 264: h1251-h1258.

bardin n, anfosso f, masse j, cramer e, sabatier f, bivic a, sampol j, dignat-george f. identification of cd146 as a component of the 15.

endothelial junction involved in the control of cell-cell cohesion. blood 2001; 98: 3677-3684.

komarova ya, mehta d, malik ab. dual regulation of endothelial junctional permeability. sci stke 2007; 2007: re8.16.

orlova vv, chavakis t. regulation of vascular endothelial permeability by junctional adhesion molecules (jam). thromb haemost 17.

2007; 98: 327-332.

bogatcheva nv, verin ad. the role of cytoskeleton in the regulation of vascular endothelial barrier function. microvasc res 2008; 18.

76: 202-207.

rao rm, yang l, garcia-cardena g, luscinskas fw. endothelial-dependent mechanisms of leukocyte recruitment to the vascular 19.

wall. circ res 2007; 101: 234-247.

salmi m, koskinen k, henttinen t, elima k, jalkanen s. clever-1 mediates lymphocyte transmigration through vascular and 20.

lymphatic endothelium. blood 2004; 104: 3849-3857.

lee tj, shirasaki y, nickols ga. altered endothelial modulation of vascular tone in aging and hypertension. blood vessels 1987; 24: 21.

132-136.

busse r, trogisch g, bassenge e. the role of endothelium in the control of vascular tone. basic res cardiol 1985; 80: 475-490.22.

highsmith rf, pang dc, rapoport rm. endothelial cell-derived vasoconstrictors: mechanisms of action in vascular smooth muscle. 23.

j cardiovasc pharmacol 1989; 13 suppl 5: s36-s44.

stalcup sa, davidson d, mellins rb. endothelial cell functions in the hemodynamic responses to stress. ann ny acad sci 1982; 401: 24.

117-131.

minami t, sugiyama a, wu sQ, abid r, kodama t, aird wc. thrombin and phenotypic modulation of the endothelium. arterioscler 25.

thromb vasc biol 2004; 24: 41-53.

weintraub ws. the pathophysiology and burden of restenosis. am j cardiol 2007; 100: s3-s9.26.

abbott wm, megerman j, hasson je, l’italien g, warnock df. effect of compliance mismatch on vascular graft patency. j vasc surg 27.

1987; 5: 376-382.

salacinski hj, goldner s, giudiceandrea a, hamilton g, seifalian a, edwards a, carson r. the mechanical behavior of vascular grafts: 28.

a review. j biomater appl 2001; 15: 241-278.

kon zn, white c, kwon mh, judy j, brown en, gu j, burris ns, laird pc, brown t, brazio ps, gammie j, brown j, griffith bp, poston 29.

rs. the role of preexisting pathology in the development of neointimal hyperplasia in coronary artery bypass grafts. j surg res

2007; 142: 351-356.

panetta tf, marin ml, veith fj, goldsmith j, gordon re, jones am, schwartz ml, gupta sk, wengerter kr. unsuspected preexisting 30.

saphenous vein disease: an unrecognized cause of vein bypass failure. j vasc surg 1992; 15: 102-110.

autieri mv. allograft-induced proliferation of vascular smooth muscle cells: potential targets for treating transplant vasculopathy. 31.

curr vasc pharmacol 2003; 1: 1-9.

herring m, gardner a, glover j. a single-staged technique for seeding vascular grafts with autogenous endothelium. surgery 1978; 32.

84: 498-504.

herring mb, dilley r, jersild ra, jr., boxer l, gardner a, glover j. seeding arterial prostheses with vascular endothelium. the nature 33.

of the lining. ann surg 1979; 190: 84-90.

weinberg cb, bell e. a blood vessel model constructed from collagen and cultured vascular cells. science 1986; 231: 397-400.34.

weinberg cb, bell e. regulation of proliferation of bovine aortic endothelial cells, smooth muscle cells, and adventitial fibroblasts 35.

in collagen lattices. j cell physiol 1985; 122: 410-414.

niklason le, gao j, abbott wm, hirschi kk, houser s, marini r, langer r. functional arteries grown 36. in Vitro. science 1999; 284:

489-493.

solan a, mitchell s, moses ma, niklason le. effect of pulse rate on collagen deposition in the tissue-engineered blood vessel. tissue 37.

eng 2003; 9: 579-586.

l’heureux n, paquet s, labbe r, germain l, auger f. a completely biological tissue-engineered human blood vessel. faseb j 1998; 38.

12: 47-56.

l’heureux n, stoclet j, auger fa, lagaud g, germain l, andriantsitohaina r. a human tissue-engineered vascular media: a new 39.

model for pharmacological studies of contractile responses. faseb j 2001; 15: 515-524.

hersel u, dahmen c, kessler h. rgd modified polymers: biomaterials for stimulated cell adhesion and beyond. biomaterials 2003; 40.

24: 4385-4415.

petrie t, capadona j, reyes c, garcia a. integrin specificity and enhanced cellular activities associated with surfaces presenting a 41.

recombinant fibronectin fragment compared to rgd supports. biomaterials 2006; 27: 5459-5470.

laflamme k, roberge cj, grenier g, rémy-zolghadri m, pouliot s, baker k, labbe r, orleans-juste p, auger fa, germain l. adventitia 42.

contribution in vascular tone: insights from adventitia-derived cells in a tissue-engineered human blood vessel. faseb j 2006;

20: 1245-1247.

huynh t, abraham g, murray j, brockbank k, hagen po, sullivan s. remodeling of an acellular collagen graft into a physiologically 43.

responsive neovessel. nat biotech 1999; 17: 1083-1086.

bouïs d, hospers ga, meijer c, molema g, mulder nh. endothelium 44. in Vitro: a review of human vascular endothelial cell lines for

blood vessel-related research. angiogenesis 2001; 4: 91-102.

unterluggauer h, hütter e, voglauer r, grillari j, vöth m, bereiter-hahn j, jansen-dürr p, jendrach m. identification of cultivation-45.

independent markers of human endothelial cell senescence in Vitro. biogerontology 2007; 8: 383-397.

asahara t, murohara t, sullivan a, silver m, vanderzee r, li t, witzenbichler b, schatteman g, isner jm. isolation of putative 46.

progenitor endothelial cells for angiogenesis. science 1997; 275: 964-967.

ingram da, mead le, tanaka h, meade v, fenoglio a, mortell k, pollok k, ferkowicz m, gilley d, yoder m. identification of a novel 47.

hierarchy of endothelial progenitor cells utilizing human peripheral and umbilical cord blood. blood 2004; 104: 2752-2760.

colton ck. implantable biohybrid artificial organs. cell transplant 1995; 4: 415-436.48.

appendices

208

references

209 App

kawamoto a, asahara t, losordo dw. transplantation of endothelial progenitor cells for therapeutic neovascularization. cardiovasc 71.

radiat med 2002; 3: 221-225.

tamaki t, uchiyama y, okada y, ishikawa t, sato m, akatsuka a, asahara t. functional recovery of damaged skeletal muscle through 72.

synchronized vasculogenesis, myogenesis, and neurogenesis by muscle-derived stem cells. circulation 2005; 112: 2857-2866.

rehman j, li jl, orschell cm, march kl. peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages 73.

and secrete angiogenic growth factors. circulation 2003; 107: 1164-1169.

rohde e, malischnik c, thaler d, maierhofer t, linkesch w, lanzer g, guelly c, strunk d. blood monocytes mimic endothelial 74.

progenitor cells. stem cells 2006; 24: 357-367.

romagnani p, annunziato f, liotta f, lazzeri e, mazzinghi b, frosali f, cosmi l, maggi l, lasagni l, scheffold a, kruger m, dimmeler 75.

s, marra f, gensini g, maggi e, romagnani s. cd14+cd34low cells with stem cell phenotypic and functional features are the major

source of circulating endothelial progenitors. circ res 2005; 97: 314-322.

schmeisser a, garlichs cd, zhang h, eskafi s, graffy c, ludwig j, strasser rh, daniel wg. monocytes coexpress endothelial and 76.

macrophagocytic lineage markers and form cord-like structures in matrigel (r) under angiogenic conditions. cardiovasc res 2001;

49: 671-680.

dankers pyw, van beek djm, ten cate at, sijbesma rp, meijer ew. novel biocompatible supramolecular materials for tissue 77.

engineering. polymeric mater 2003; 88: 52-53.

dankers pyw, harmsen mc, brouwer la, van luyn mja, meijer ew. a modular and supramolecular approach to bioactive scaffolds 78.

for tissue engineering. nat mater 2005; 4: 568-574.

heijkants rg, van calck rv, de groot jh, pennings aj, schouten aj, van tienen tg, ramrattan n, buma p, veth rp. design, synthesis 79.

and properties of a degradable polyurethane scaffold for meniscus regeneration. j mater sci mater med 2004; 15: 423-427.

hynes ro. a reevaluation of integrins as regulators of angiogenesis. nat med 2002; 8: 918-921.80.

de fougerolles ar, koteliansky ve. regulation of monocyte gene expression by the extracellular matrix and its functional 81.

implications. immunol rev 2002; 186: 208-220.

folmer bjb, sijbesma rp, versteegen rm, van der rijt jaj, meijer ew. supramolecular polymer materials: chain extension of telechelic 82.

polymers using a reactive hydrogen-bonding synthon. adv mater 2000; 12: 874-878.

davis lg, dibner md, battey jf. optical density analytical measurements. in: davis lg, dibner md, battey jf, editors. basic methods 83.

in molecular biology. new york: elsevier, 1986. p. 327-328.

heijkants r. ph.d. thesis: polyurethane scaffold as meniscus reconstruction materials. rijksuniversiteit groningen, the netherlands, 84.

2004.

li t, hamano k, nishida m, hayashi m, ito h, mikamo a, matsuzaki m. cd11785. + stem cells play a key role in therapeutic angiogenesis

induced by bone marrow cell implantation. am j physiol heart circ physiol 2003; 285: h931-h937.

Quirici n, soligo d, caneva l, servida f, bossolasco p, deliliers g. differentiation and expansion of endothelial cells from human bone 86.

marrow cd133+ cells. br j haematol 2001; 115: 186-194.

fujiyama s, amano k, uehira k, yoshida m, nishiwaki y, nozawa y, jin d, takai s, miyazaki m, egashira k, imada t, iwasaka t, 87.

matsubara h. bone marrow monocyte lineage cells adhere on injured endothelium in a monocyte chemoattractant protein-1-

dependent manner and accelerate reendothelialization as endothelial progenitor cells. circ res 2003; 93: 980-989.

fernandez pujol b, lucibello fc, zuzarte m, lutjens p, muller r, havemann k. dendritic cells derived from peripheral monocytes 88.

express endothelial markers and in the presence of angiogenic growth factors differentiate into endothelial-like cells. eur j cell

biol 2001; 80: 99-110.

fernandez pujol b, lucibello fc, gehling um, lindemann k, weidner n, zuzarte ml, adamkiewicz j, elsasser hp, muller r, havemann 89.

k. endothelial-like cells derived from human cd14 positive monocytes. differentiation 2000; 65: 287-300.

zhao y, glesne d, huberman e. a human peripheral blood monocyte-derived subset acts as pluripotent stem cells. proc natl acad 90.

sci u s a 2003; 100: 2426-2431.

zhao y, mazzone t. human umbilical cord blood-derived f-macrophages retain pluripotentiality after thrombopoietin expansion. 91.

exp cell res 2005; 310: 311-318.

zumstein a, mathieu o, howald h, hoppeler h. morphometric analysis of the capillary supply in skeletal muscles of trained and 49.

untrained subjects - its limitations in muscle biopsies. pflügers archiv european journal of physiology 1983; 397: 277-283.

lopez jj, laham rj, stamler a, pearlman jd, bunting s, kaplan a, carrozza jp, sellke fw, simons m. vegf administration in chronic 50.

myocardial ischemia in pigs. cardiovasc res 1998; 40: 272-281.

sato k, wu t, laham rj, johnson rb, douglas p, li j, sellke fw, bunting s, simons m, post mj. efficacy of intracoronary or intravenous 51.

vegf165 in a pig model of chronic myocardial ischemia. j am coll cardiol 2001; 37: 616-623.

hariawala md, horowitz jr, esakof d, sheriff dd, walter dh, keyt b, isner jm, symes jf. vegf improves myocardial blood flow but 52.

produces edrf-mediated hypotension in porcine hearts. j surg res 1996; 63: 77-82.

rabinovsky e, draghia-akli r. insulin-like growth factor i plasmid therapy promotes 53. in Vivo angiogenesis. mol ther 2004; 9:

46-55.

mack ca, magovern cj, budenbender kt, patel sr, schwarz ea, zanzonico p, ferris b, sanborn t, isom p, ferris b, sanborn t, isom 54.

ow, crystal rg, rosengart tk. salvage angiogenesis induced by adenovirus-mediated gene transfer of vascular endothelial growth

factor protects against ischemic vascular occlusion. j vasc surg 1998; 27: 699-709.

choi j, hur j, yoon c, kim j, lee c, youn s, oh i, skurk c, murohara t, park y, walsh k, kim h. augmentation of therapeutic angiogenesis 55.

using genetically-modified human endothelial progenitor cells with altered glycogen synthase kinase-3beta activity. j biol chem

2004; 279: 49430-49438.

lu y, shansky j, del tatto m, ferland p, wang x, vandenburgh h. recombinant vascular endothelial growth factor secreted from 56.

tissue-engineered bioartificial muscles promotes localized angiogenesis. circulation 2001; 104: 594-599.

sakamoto t, spee c, scuric z, gordon em, hinton dr, anderson wf, ryan sj. ability of retroviral transduction to modify the 57.

angiogenic characteristics of rpe cells. graefes arch clin exp ophthalmol 1998; 236: 220-229.

lee rj, springer ml, blanco-bose we, shaw r, ursell pc, blau hm. vegf gene delivery to myocardium: deleterious effects of 58.

unregulated expression. circulation 2000; 102: 898-901.

sheridan mh, shea ld, peters mc, mooney dj. bioabsorbable polymer scaffolds for tissue engineering capable of sustained growth 59.

factor delivery. j control release 2000; 64: 91-102.

wu x, rabkin-aikawa e, guleserian k, perry t, masuda y, sutherland f, schoen f, mayer je, jr., bischoff j. tissue-engineered 60.

microvessels on three-dimensional biodegradable scaffolds using human endothelial progenitor cells. am j physiol heart circ

physiol 2004; 287: h480-h487.

kalka c, masuda h, takahashi t, kalka-moll w, silver m, kearney m, li t, isner jm, asahara t. transplantation of ex vivo expanded 61.

endothelial progenitor cells for therapeutic neovascularization. proc natl acad sci u s a 2000; 97: 3422-3427.

hur j, yoon c, kim h, choi j, kang h, hwang k, oh bh, lee m, park y. characterization of two types of endothelial progenitor cells and 62.

their different contributions to neovasculogenesis. arterioscler thromb vasc biol 2004; 24: 288-293.

yoder m, mead le, prater d, krier t, mroueh k, li f, krasich r, temm c, prchal j, ingram da. redefining endothelial progenitor cells 63.

via clonal analysis and hematopoietic stem/progenitor cell principals. blood 2007; 109: 1801-1809.

awad o, dedkov e, jiao c, bloomer s, tomanek r, schatteman g. differential healing activities of cd3464. + and cd14+ endothelial cell

progenitors. arterioscler thromb vasc biol 2006; 26: 758-764.

heil m, ziegelhoeffer t, mees b, schaper w. a different outlook on the role of bone marrow stem cells in vascular growth - bone 65.

marrow delivers software not hardware. circ res 2004; 94: 573-574.

sayers rd, raptis s, berce m, miller jh. long-term results of femorotibial bypass with vein or polytetrafluoroethylene. br j surg 66.

1998; 85: 934-938.

meinhart jg, schense jc, schima h, gorlitzer m, hubbell ja, deutsch m, zilla p. enhanced endothelial cell retention on shear-stressed 67.

synthetic vascular grafts precoated with rgd-cross-linked fibrin. tissue eng 2005; 11: 887-895.

unger re, peters k, wolf m, motta a, migliaresi c, kirkpatrick cj. endothelialization of a non-woven silk fibroin net for use in tissue 68.

engineering: growth and gene regulation of human endothelial cells. biomaterials 2004; 25: 5137-5146.

conklin bs, wu h, lin ph, lumsden ab, chen c. basic fibroblast growth factor coating and endothelial cell seeding of a decellularized 69.

heparin-coated vascular graft. artif organs 2004; 28: 668-675.

asahara t, kawamoto a. endothelial progenitor cells for postnatal vasculogenesis. am j physiol cell physiol 2004; 287: c572-c579.70.

appendices

210

references

211 App

national kidney foundation. k/doQi clinical practice guidelines for chronic kidney disease: evaluation, classification, and 112.

stratification. am j kidney dis 2002; 39: s1-266.

krenning g, van der strate bwa, schipper m, gallego y van seijen xj, fernandes b, van luyn mja, harmsen mc. cd34113. + cells augment

endothelial cell differentiation of cd14+ endothelial progenitor cells in Vitro. j cell mol med 2008; in press.

sturiale a, coppolino g, loddo s, criseo m, campo s, crasci e, bolignano d, nostro l, teti d, buemi m. effects of haemodialysis on 114.

circulating endothelial progenitor cell count. blood purif 2007; 25: 242-251.

freedman mh, cattran dc, saunders ef. anemia of chronic renal failure: inhibition of erythropoiesis by uremic serum. nephron 115.

1983; 35: 15-19.

hotta t, maeda h, suzuki i, chung tg, saito a. selective inhibition of erythropoiesis by sera from patients with chronic renal failure. 116.

proc soc exp biol med 1987; 186: 47-51.

westerweel pe, hoefer ie, blankestijn pj, de bree p, groeneveld d, van oostrom o, braam b, koomans ha, verhaar mc. end-stage 117.

renal disease causes an imbalance between endothelial and smooth muscle progenitor cells. am j physiol renal physiol 2007; 292:

f1132-f1140.

de groot k, hermann bahlmann f, sowa j, koenig j, menne j, haller h, fliser d. uremia causes endothelial progenitor cell deficiency. 118.

kidney int 2004; 66: 641-646.

coppolino g, bolignano d, campo s, loddo s, teti d, buemi m. circulating progenitor cells after cold pressor test in hypertensive and 119.

uremic patients. hypertension research 2008; 31: 717-724.

stinghen ae, goncalves sm, martines eg, nakao ls, riella mc, aita ca, pecoits-filho r. increased plasma and endothelial cell 120.

expression of chemokines and adhesion molecules in chronic kidney disease. nephron clin pract 2009; 111: c117-c126.

jacobson sh, egberg n, hylander b, lundahl j. correlation between soluble markers of endothelial dysfunction in patients with 121.

renal failure. am j nephrol 2002; 22: 42-47.

umland o, heine h, miehe m, marienfeld k, staubach k, ulmer a. induction of various immune modulatory molecules in cd34122. +

hematopoietic cells. j leukoc biol 2004; 75: 671-679.

vasa m, fichtlscherer s, adler k, aicher a, martin h, zeiher a, dimmeler s. increase in circulating endothelial progenitor cells by 123.

statin therapy in patients with stable coronary artery disease. circulation 2001; 103: 2885-2890.

walter d, rittig k, bahlmann fh, kirchmair r, silver m, murayama t, nishimura h, losordo dw, asahara t, isner jm. statin therapy 124.

accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial

progenitor cells. circulation 2002; 105: 3017-3024.

bahlmann fh, degroot k, duckert t, niemczyk e, bahlmann e, boehm sm, haller h, fliser d. endothelial progenitor cell proliferation 125.

and differentiation is regulated by erythropoietin. kidney int 2003; 64: 1648-1652.

shepherd j, kastelein jjp, bittner v, deedwania p, breazna a, dobson s, wilson dj, zuckerman a, wenger nk, for the treating to 126.

new targets investigators. effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart

disease: the treating to new targets (tnt) study. clin j am soc nephrol 2007; 2: 1131-1139.

shepherd j, kastelein jjp, bittner v, deedwania p, breazna a, dobson s, wilson dj, zuckerman a, wenger nk. intensive lipid lowering 127.

with atorvastatin in patients with coronary heart disease and chronic kidney disease: the tnt (treating to new targets) study. j

am coll cardiol 2008; 51: 1448-1454.

shepherd j, barter p, carmena r, deedwania p, fruchart jc, haffner s, hsia j, breazna a, larosa j, grundy s, waters d, for the treating 128.

to new targets investigators. effect of lowering ldl cholesterol substantially below currently recommended levels in patients

with coronary heart disease and diabetes: the treating to new targets (tnt) study. diabetes care 2006; 29: 1220-1226.

wattanakit k, cushman m, stehman-breen c, heckbert sr, folsom ar. chronic kidney disease increases risk for venous 129.

thromboembolism. j am soc nephrol 2008; 19: 135-140.

mahmoodi bk, ten kate mk, waanders f, veeger nj, brouwer jl, vogt l, navis g, van der mj. high absolute risks and predictors of 130.

venous and arterial thromboembolic events in patients with nephrotic syndrome: results from a large retrospective cohort study.

circulation 2008; 117: 224-230.

stenvinkel p, ekstrom tj. epigenetics and the uremic phenotype: a matter of balance. contrib nephrol 2008; 161: 55-62.131.

stenvinkel p, ekstrom tj. does the uremic milieu affect the epigenotype? j ren nutr 2009; 19: 82-85.132.

christenson em, dadsetan m, wiggins m, anderson jm, hiltner a. poly(carbonate urethane) and poly(ether urethane) biodegradation: 92.

in Vivo studies. j biomed mater res a 2004; 69a: 407-416.

matheson la, santerre jp, labow rs. changes in macrophage function and morphology due to biomedical polyurethane surfaces 93.

undergoing biodegradation. j cell physiol 2004; 199: 8-19.

danen ehj, sonneveld p, brakebusch c, fassler r, sonnenberg a. the fibronectin-binding integrins a5b1 and avb3 differentially 94.

modulate rhoa-gtp loading, organization of cell matrix adhesions, and fibronectin fibrillogenesis. j cell biol 2002; 159:

1071-1086.

eliceiri b, cheresh d. the role of av integrins during angiogenesis: insights into potential mechanisms of action and clinical 95.

development. j clin invest 1999; 103: 1227-1230.

sijbesma rp, meijer ew. Quadruple hydrogen bonded systems. chem commun 2003; 5-16.96.

dankers pyw, van leeuwen enm, van gemert gml, spiering ajh, harmsen mc, brouwer la, janssen hm, bosman aw, van luyn 97.

mja, meijer ew. chemical and biological properties of supramolecular polymer systems based on oligocaprolactones. biomaterials

2006; 27: 5490-5501.

werner n, nickenig g. endothelial progenitor cells in health and atherosclerotic disease. ann med 2007; 39: 82-90.98.

dimmeler s, zeiher am. vascular repair by circulating endothelial progenitor cells: the missing link in atherosclerosis? j mol med 99.

2004; 82: 671-677.

popa er, harmsen mc, tio ra, van der strate bwa, brouwer la, schipper m, koerts j, de jongste mjl, hazenberg a, hendriks m, 100.

van luyn mja. circulating cd34+ progenitor cells modulate host angiogenesis and inflammation in Vivo. j mol cell cardiol 2006;

41: 86-96.

krenning g, dankers pyw, jovanovic d, van luyn mja, harmsen mc. efficient differentiation of cd14101. + monocytic cells into endothelial

cells on degradable biomaterials. biomaterials 2007; 28: 1470-1479.

krenning g, van luyn mja, harmsen mc. endothelial progenitor cell-based neovascularization: implications for therapy. trends 102.

mol med 2009; in press.

mall j, philipp aw, rademacher a, paulitschke m, buttemeyer r. re-endothelialization of punctured eptfe graft: an 103. in Vitro study

under pulsed perfusion conditions. nephrol dial transplant 2004; 19: 61-67.

kaushal s, amiel ge, guleserian kj, shapira om, perry t, sutherland fw, rabkin e, moran am, schoen fj, atala a, soker s, bischoff 104.

j, mayer je, jr. functional small-diameter neovessels created using endothelial progenitor cells expanded ex vivo. nat med 2001;

7: 1035-1040.

krenning g, moonen jraj, van luyn mja, harmsen mc. generating new blood flow: integrating developmental biology and tissue 105.

engineering. trends cardiovasc med 2009; in press.

sarnak mj, levey as, schoolwerth ac, coresh j, culleton b, hamm ll, mccullough pa, kasiske bl, kelepouris e, klag mj, parfrey p, 106.

pfeffer m, raij l, spinosa dj, wilson pw. kidney disease as a risk factor for development of cardiovascular disease: a statement from

the american heart association councils on kidney in cardiovascular disease, high blood pressure research, clinical cardiology, and

epidemiology and prevention. circulation 2003; 108: 2154-2169.

shishehbor mh, oliveira lpj, lauer ms, sprecher dl, wolski k, cho l, hoogwerf bj, hazen sl. emerging cardiovascular risk factors 107.

that account for a significant portion of attributable mortality risk in chronic kidney disease. am j cardiol 2008; 101: 1741-1746.

moonen jraj, de leeuw k, van seijen x, kallenberg c, van luyn mja, bijl m, harmsen mc. reduced number and impaired function of 108.

circulating progenitor cells in patients with systemic lupus erythematosus. arthritis res ther 2007; 9: r84.

valgimigli m, rigolin gm, fucili a, porta md, soukhomovskaia o, malagutti p, bugli am, bragotti lz, francolini g, mauro e, castoldi 109.

g, ferrari r. cd34+ and endothelial progenitor cells in patients with various degrees of congestive heart failure. circulation 2004;

110: 1209-1212.

choi jh, kim kl, huh w, kim b, byun j, suh w, sung j, jeon es, oh hy, kim dk. decreased number and impaired angiogenic function 110.

of endothelial progenitor cells in patients with chronic renal failure. arterioscler thromb vasc biol 2004; 24: 1246-1252.

rodriguez-ayala e, yao Q, holmen c, lindholm b, sumitran-holgersson s, stenvinkel p. imbalance between detached circulating 111.

endothelial cells and endothelial progenitor cells in chronic kidney disease. blood purif 2006; 24: 196-202.

appendices

212

references

213 App

ishisaki a, hayashi h, li aj, imamura t. human umbilical vein endothelium-derived cells retain potential to differentiate into 155.

smooth muscle-like cells. j biol chem 2003; 278: 1303-1309.

lancrin c, sroczynska p, stephenson c, allen t, kouskoff v, lacaud g. the haemangioblast generates haematopoietic cells through 156.

a haemogenic endothelium stage. nature 2009; 457: 892-895.

hellstrom m, kalen m, lindahl p, abramsson a, betsholtz c. role of pdgf-b and pdgfr-b in recruitment of vascular smooth muscle 157.

cells and pericytes during embryonic blood vessel formation in the mouse. development 1999; 126: 3047-3055.

hirschi kk, rohovsky sa, d’amore pa. pdgf, tgf-b, and heterotypic cell-cell interactions mediate endothelial cell-induced 158.

recruitment of 10t1/2 cells and their differentiation to a smooth muscle fate. j cell biol 1998; 141: 805-814.

yamashita j, itoh h, hirashima m, ogawa m, nishikawa si, yurugi t, naito m, nakao k, nishikawa si. flk1-positive cells derived from 159.

embryonic stem cells serve as vascular progenitors. nature 2000; 408: 92-96.

ferreira ls, gerecht s, shieh h, watson n, rupnick m, dallabrida s, vunjak-novakovic g, langer r. vascular progenitor cells isolated 160.

from human embryonic stem cells give rise to endothelial and smooth muscle like cells and form vascular networks In Vivo. circ

res 2007; 101: 286-294.

markwald rr, fitzharris tp, manasek fj. structural development of endocardial cushions. am j anat 1977; 148: 85-119.161.

arciniegas e, sutton ab, allen td, schor am. transforming growth factor-b1 promotes the differentiation of endothelial cells into 162.

smooth muscle-like cells in Vitro. j cell sci 1992; 103 ( pt 2): 521-529.

deissler h, deissler h, lang gk, lang ge. tgfb induces transdifferentiation of ibrec to asma-expressing cells. int j mol med 2006; 163.

18: 577-582.

frid mg, kale v, stenmark k. mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal 164.

transdifferentiation: In Vitro analysis. circ res 2002; 90: 1189-1196.

krenning g, moonen jraj, van luyn mja, harmsen mc. vascular smooth muscle cells for use in vascular tissue engineering obtained 165.

by endothelial-to-mesenchymal transdifferentiation (enmt) on collagen matrices. biomaterials 2008; 29: 3703-3711.

zeisberg em, tarnavski o, zeisberg m, dorfman al, mcmullen jr, gustafsson e, chandraker a, yuan x, pu wt, roberts ab, neilson eg, 166.

sayegh mh, izumo s, kalluri r. endothelial-to-mesenchymal transition contributes to cardiac fibrosis. nat med 2007; 13: 952-961.

oswald j, boxberger s, jorgensen b, feldmann s, ehninger g, bornhauser m, werner c. mesenchymal stem cells can be differentiated 167.

into endothelial cells In Vitro. stem cells 2004; 22: 377-384.

wang h, riha gm, yan s, li m, chai h, yang h, yao Q, chen c. shear stress induces endothelial differentiation from a murine embryonic 168.

mesenchymal progenitor cell line. arterioscler thromb vasc biol 2005; 25: 1817-1823.

popa er, van der strate bwa, brouwer la, tadema h, schipper m, fernandes b, hendriks m, van luyn mja, harmsen mc. dependence 169.

of neovascularization mechanisms on the molecular microenvironment. tissue eng 2007; 13: 2913-2921.

hirschi kk, ingram da, yoder mc. assessing identity, phenotype, and fate of endothelial progenitor cells. arterioscler thromb vasc 170.

biol 2008; 28: 1584-1595.

fukata y, amano m, kaibuchi k. rho-rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-171.

muscle cells. trends pharmacol sci 2001; 22: 32-39.

goumans mj, valdimarsdottir g, itoh s, lebrin f, larsson j, mummery cl, karlsson s, ten dp. activin receptor-like kinase (alk)1 is 172.

an antagonistic mediator of lateral tgfb/alk5 signaling. mol cell 2003; 12: 817-828.

norton jd. id helix-loop-helix proteins in cell growth, differentiation and tumorigenesis. j cell sci 2000; 113 ( pt 22): 3897-3905.173.

ruzinova mb, benezra r. id proteins in development, cell cycle and cancer. trends cell biol 2003; 13: 410-418.174.

saika s, ikeda k, yamanaka o, flanders kc, ohnishi y, nakajima y, muragaki y, ooshima a. adenoviral gene transfer of bmp-7, id2, 175.

or id3 suppresses injury-induced epithelial-to-mesenchymal transition of lens epithelium in mice. am j physiol cell physiol 2006;

290: c282-c289.

kowanetz m, valcourt u, bergstrom r, heldin ch, moustakas a. id2 and id3 define the potency of cell proliferation and differentiation 176.

responses to transforming growth factor beta and bone morphogenetic protein. mol cell biol 2004; 24: 4241-4254.

arras m, ito wd, scholz d, winkler b, schaper j, schaper w. monocyte activation in angiogenesis and collateral growth in the rabbit 177.

hindlimb. j clin invest 1998; 101: 40-50.

dahl sl, koh j, prabhakar v, niklason le. decellularized native and engineered arterial scaffolds for transplantation. cell transplant 133.

2003; 12: 659-666.

wu h, wang t, kang p, tsuang y, sun j, lin f. coculture of endothelial and smooth muscle cells on a collagen membrane in the 134.

development of a small-diameter vascular graft. biomaterials 2007; 28: 1385-1392.

matsuda t. recent progress of vascular graft engineering in japan. artif organs 2004; 28: 64-71.135.

rezai n, podor tj, mcmanus bm. bone marrow cells in the repair and modulation of heart and blood vessels: emerging opportunities 136.

in native and engineered tissue and biomechanical materials. artif organs 2004; 28: 142-151.

melero-martin j, khan z, picard a, wu x, paruchuri s, bischoff j. 137. In Vivo vasculogenic potential of human blood-derived endothelial

progenitor cells. blood 2007; 109: 4761-4768.

schmidt d, mol a, neuenschwander s, breymann c, gossi m, zund g, turina m, hoerstrup sp. living patches engineered from human 138.

umbilical cord derived fibroblasts and endothelial progenitor cells. eur j cardiothorac surg 2005; 27: 795-799.

simper d, stalboerger p, panetta c, wang s, caplice n. smooth muscle progenitor cells in human blood. circulation 2002; 106: 139.

1199-1204.

sugiyama s, kugiyama k, nakamura s, kataoka k, aikawa m, shimizu k, koide s, mitchell r, ogawa h, libby p. characterization of 140.

smooth muscle-like cells in circulating human peripheral blood. atherosclerosis 2006; 187: 351-362.

liu c, nath k, katusic z, caplice n. smooth muscle progenitor cells in vascular disease. trends cardiovasc med 2004; 14: 288-293.141.

kashiwakura y, katoh y, tamayose k, konishi h, takaya n, yuhara s, yamada m, sugimoto k, daida h. isolation of bone marrow stromal 142.

cell-derived smooth muscle cells by a human sm22a promoter: In Vitro differentiation of putative smooth muscle progenitor cells of

bone marrow. circulation 2003; 107: 2078-2081.

mercado-pimentel me, hubbard ad, runyan rb. endoglin and alk5 regulate epithelial-mesenchymal transformation during cardiac 143.

valve formation. dev biol 2007; 304: 420-432.

paranya g, vineberg s, dvorin e, kaushal s, roth s, rabkin e, schoen fj, bischoff j. aortic valve endothelial cells undergo transforming 144.

growth factor-b-mediated and non-transforming growth factor-b-mediated transdifferentiation in Vitro. am j pathol 2001; 159:

1335-1343.

noseda m, mclean g, niessen k, chang l, pollet i, montpetit r, shahidi r, dorovini-zis k, li l, beckstead b, durand re, hoodless 145.

pa, karsan a. notch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal

transformation. circ res 2004; 94: 910-917.

burgess wh, mehlman t, friesel r, johnson wv, maciag t. multiple forms of endothelial cell growth factor. rapid isolation and 146.

biological and chemical characterization. j biol chem 1985; 260: 11389-11392.

van oeveren w, haan j, lagerman p, schoen t. comparison of coagulation activity tests 147. in Vitro for selected biomaterials. artif

organs 2002; 26: 506-511.

kakisis j, liapis c, breuer c, sumpio b. artificial blood vessel: the holy grail of peripheral vascular surgery. j vasc surg 2005; 41: 148.

349-354.

koike n, fukumura d, gralla o, au p, schechner j, jain rk. tissue engineering: creation of long-lasting blood vessels. nature 2004; 149.

428: 138-139.

zeisberg em, potenta s, xie l, zeisberg m, kalluri r. discovery of endothelial to mesenchymal transition as a source for carcinoma-150.

associated fibroblasts. cancer res 2007; 67: 10123-10128.

deruiter mc, poelmann re, vanmunsteren jc, mironov v, markwald rr, gittenberger-de groot ac. embryonic endothelial cells 151.

transdifferentiate into mesenchymal cells expressing smooth muscle actins in Vivo and in Vitro. circ res 1997; 80: 444-451.

fernandes dj, ravenhall ce, harris t, tran t, vlahos r, stewart ag. contribution of the p38mapk signalling pathway to proliferation 152.

in human cultured airway smooth muscle cells is mitogen-specific. br j pharmacol 2004; 142: 1182-1190.

ferrari g, pintucci g, seghezzi g, hyman km, galloway ac, mignatti p. vegf, a prosurvival factor, acts in concert with tgf-b1 to 153.

induce endothelial cell apoptosis. proc natl acad sci u s a 2006; 103: 17260-17265.

hyman km, seghezzi g, pintucci g, stellari g, kim jh, grossi ea, galloway ac, mignatti p. transforming growth factor-β1 induces 154.

apoptosis in vascular endothelial cells by activation of mitogen-activated protein kinase. surgery 2002; 132: 173-179.

appendices

214

references

215 App

igreja c, fragoso r, caiado f, clode n, henriques a, camargo l, reis em, dias s. detailed molecular characterization of cord blood-198.

derived endothelial progenitors. exp hematol 2008; 36: 193.

zentilin l, taturo s, zacchigna s, arsic n, pattarini l, sinigaglia m, giacca m. bone marrow mononuclear cells are recruited to the 199.

sites of vegf-induced neovascularization but are not incorporated into the newly formed vessels. blood 2006; 107: 3546-3554.

botta r, gao e, stassi g, bonci d, pelosi e, zwas d, patti m, colonna l, baiocchi m, coppola s, ma x, condorelli g, peschle c. heart 200.

infarct in nod-scid mice: therapeutic vasculogenesis by transplantation of human cd34+ cells and low dose cd34+kdr+ cells.

faseb j 2004; 18: 1392-1394.

tei k, matsumoto t, mifune y, ishida k, sasaki k, shoji t, kubo s, kawamoto a, asahara t, kurosaka m, kuroda r. administrations 201.

of peripheral blood cd34-positive cells contribute to medial collateral ligament healing via vasculogenesis. stem cells 2008;

2007-0671.

yoon c, hur j, park k, kim j, lee c, oh i, kim t, cho h, kang h, chae i, yang h, oh bh, park y, kim h. synergistic neovascularization by 202.

mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: the role of angiogenic cytokines

and matrix metalloproteinases. circulation 2005; 112: 1618-1627.

o’riordan e, mendelev n, patschan s, patschan d, eskander j, cohen-gould l, chander p, goligorsky ms. chronic nos inhibition 203.

actuates endothelial-mesenchymal transformation. am j physiol heart circ physiol 2007; 292: h285-h294.

arciniegas e, frid mg, douglas is, stenmark kr. perspectives on endothelial-to-mesenchymal transition: potential contribution to 204.

vascular remodeling in chronic pulmonary hypertension. am j physiol lung cell mol physiol 2007; 293: l1-l8.

sakao s, taraseviciene-stewart l, cool c, tada y, kasahara y, kurosu k, tanabe n, takiguchi y, tatsumi k, kuriyama t, voelkel n. 205.

vegf-r blockade causes endothelial cell apoptosis, expansion of surviving cd34+ precursor cells and transdifferentiation to smooth

muscle-like and neuronal-like cells. faseb j 2007; 21: 3640-3652.

krug el, mjaatvedt ch, markwald rr. extracellular matrix from embryonic myocardium elicits an early morphogenetic event in 206.

cardiac endothelial differentiation. dev biol 1987; 120: 348-355.

taipale j, keski-oja j. growth factors in the extracellular matrix. faseb j 1997; 11: 51-59.207.

duong td, erickson ca. mmp-2 plays an essential role in producing epithelial-mesenchymal transformations in the avian embryo. 208.

dev dyn 2004; 229: 42-53.

song w, jackson k, mcguire pg. degradation of type iv collagen by matrix metalloproteinases is an important step in the epithelial-209.

mesenchymal transformation of the endocardial cushions. dev biol 2000; 227: 606-617.

ishihara h, kubota h, lindberg rl, leppert d, gloor sm, errede m, virgintino d, fontana a, yonekawa y, frei k. endothelial cell barrier 210.

impairment induced by glioblastomas and transforming growth factor β2 involves matrix metalloproteinases and tight junction

proteins. j neuropathol exp neurol 2008; 67: 435-448.

reddy k, mangale ss. integrin receptors: the dynamic modulators of endometrial function. tissue cell 2003; 35: 260-273.211.

frank r, adelmann-grill bc, herrmann k, haustein uf, petri jb, heckmann m. transforming growth factor-b controls cell-matrix 212.

interaction of microvascular dermal endothelial cells by downregulation of integrin expression. j invest dermatol 1996; 106:

36-41.

lee yh, kayyali us, sousa am, rajan t, lechleider rj, day rm. transforming growth factor-β1 effects on endothelial monolayer 213.

permeability involve focal adhesion kinase/src. am j respir cell mol biol 2007; 37: 485-493.

olsson ak, dimberg a, kreuger j, claesson-welsh l. vegf receptor signalling - in control of vascular function. nat rev mol cell biol 214.

2006; 7: 359-371.

lampugnani m, orsenigo f, gagliani mc, tacchetti c, dejana e. vascular endothelial cadherin controls vegfr-2 internalization and 215.

signaling from intracellular compartments. j cell biol 2006; 174: 593-604.

calera mr, venkatakrishnan a, kazlauskas a. ve-cadherin increases the half-life of vegf receptor 2. exp cell res 2004; 300: 216.

248-256.

ha ch, bennett am, jin zg. a novel role of vascular endothelial cadherin in modulating c-src activation and downstream signaling 217.

of vascular endothelial growth factor. j biol chem 2008; 283: 7261-7270.

zhang xf, groopman je, wang jf. extracellular matrix regulates endothelial functions through interaction of vegfr-3 and integrin 218.

a5b1. j cell physiol 2005; 202: 205-214.

de falco e, porcelli d, torella ar, straino s, iachininoto mg, orlandi a, truffa s, biglioli p, napolitano m, capogrossi mc, pesce m. 178.

sdf-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells. blood 2004; 104:

3472-3482.

zemani f, silvestre js, fauvel-lafeve f, bruel a, vilar j, bieche i, laurendeau i, galy-fauroux i, fischer am, boisson-vidal c. ex vivo 179.

priming of endothelial progenitor cells with sdf-1 before transplantation could increase their proangiogenic potential. arterioscler

thromb vasc biol 2008; 28: 644-650.

rafii s, lyden d. therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. nat med 2003; 180.

9: 702-712.

caplice n, bunch tj, stalboerger p, wang s, simper d, miller d, russell s, litzow m, edwards w. smooth muscle cells in human 181.

coronary atherosclerosis can originate from cells administered at marrow transplantation. proc natl acad sci u s a 2003; 100:

4754-4759.

le ricousse-roussanne s, barateau v, contreres j, boval b, kraus-berthier l, tobelem g. ex vivo differentiated endothelial and 182.

smooth muscle cells from human cord blood progenitors home to the angiogenic tumor vasculature. cardiovasc res 2004; 62:

176-184.

zengin e, chalajour f, gehling um, ito wd, treede h, lauke h, weil j, reichenspurner h, kilic n, ergun s. vascular wall resident 183.

progenitor cells: a source for postnatal vasculogenesis. development 2006; 133: 1543-1551.

rajantie i, ilmonen m, alminaite a, ozerdem u, alitalo k, salven p. adult bone marrow-derived cells recruited during angiogenesis 184.

comprise precursors for periendothelial vascular mural cells. blood 2004; 104: 2084-2086.

purhonen s, palm j, rossi dj, kaskenpaa n, rajantie i, yla-herttuala s, alitalo k, weissman il, salven p. bone marrow-derived 185.

circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. proc natl acad

sci u s a 2008; 105: 6620-6625.

libby p, ridker pm, maseri a. inflammation and atherosclerosis. circulation 2002; 105: 1135-1143.186.

volger ol, fledderus jo, kisters n, fontijn rd, moerland pd, kuiper j, van berkel tj, bijnens ap, daemen mj, pannekoek h, horrevoets 187.

aj. distinctive expression of chemokines and transforming growth factor-b signaling in human arterial endothelium during

atherosclerosis. am j pathol 2007; 171: 326-337.

zoll j, fontaine v, gourdy p, barateau v, vilar j, leroyer a, lopes-kam i, mallat z, arnal jf, henry p, tobelem g, tedgui a. role of human 188.

smooth muscle cell progenitors in atherosclerotic plaque development and composition. cardiovasc res 2008; 77: 471-480.

foubert p, matrone g, souttou b, lere-dean c, barateau v, plouet j, le ricousse-roussanne s, levy bi, silvestre js, tobelem g. 189.

coadministration of endothelial and smooth muscle progenitor cells enhances the efficiency of proangiogenic cell-based therapy.

circ res 2008; 103: 751-760.

kawamoto a, losordo dw. endothelial progenitor cells for cardiovascular regeneration. trends cardiovasc med 2008; 18: 33-37.190.

liebner s, cattelino a, gallini r, rudini n, iurlaro m, piccolo s, dejana e. b-catenin is required for endothelial-mesenchymal 191.

transformation during heart cushion development in the mouse. j cell biol 2004; 166: 359-367.

arciniegas e, ponce l, hartt y, graterol a, carlini rg. intimal thickening involves transdifferentiation of embryonic endothelial cells. 192.

anat rec 2000; 258: 47-57.

hall sm, hislop aa, haworth sg. origin, differentiation, and maturation of human pulmonary veins. am j respir cell mol biol 2002; 193.

26: 333-340.

kawamoto a, asahara t. role of progenitor endothelial cells in cardiovascular disease and upcoming therapies. catheter cardiovasc 194.

interv 2007; 70: 477-484.

hill j, zalos g, halcox j, schenke w, waclawiw m, Quyyumi aa, finkel t. circulating endothelial progenitor cells, vascular function, 195.

and cardiovascular risk. n engl j med 2003; 348: 593-600.

zhang sj, zhang h, wei yj, su wj, liao zk, hou m, zhou jy, hu ss. adult endothelial progenitor cells from human peripheral blood 196.

maintain monocyte/macrophage function throughout in Vitro culture. cell res 2006; 16: 577-584.

smadja dm, basire a, amelot a, conte a, bieche i, le bonniec bf, aiach m, gaussem p. thrombin bound to a fibrin clot confers 197.

angiogenic and hemostatic properties on endothelial progenitor cells. j cell mol med 2008; 12: 975-986.

appendices

216

references

217 App

sarkar s, lee gy, wong jy, desai ta. development and characterization of a porous micro-patterned scaffold for vascular tissue 240.

engineering applications. biomaterials 2006; 27: 4775-4782.

isenberg bc, tsuda y, williams c, shimizu t, yamato m, okano t, wong jy. a thermoresponsive, microtextured substrate for cell 241.

sheet engineering with defined structural organization. biomaterials 2008; 29: 2565-2572.

choi js, lee sj, christ gj, atala a, yoo jj. the influence of electrospun aligned poly(epsilon-caprolactone)/collagen nanofiber 242.

meshes on the formation of self-aligned skeletal muscle myotubes. biomaterials 2008; 29: 2899-2906.

thomas v, jose mv, chowdhury s, sullivan jf, dean dr, vohra yk. mechano-morphological studies of aligned nanofibrous scaffolds 243.

of polycaprolactone fabricated by electrospinning. j biomater sci polym ed 2006; 17: 969-984.

vasita r, shanmugam ik, katt ds. improved biomaterials for tissue engineering applications: surface modification of polymers. curr 244.

top med chem 2008; 8: 341-353.

feng y, mrksich m. the synergy peptide phsrn and the adhesion peptide rgd mediate cell adhesion through a common mechanism. 245.

biochemistry 2004; 43: 15811-15821.

zamora po, eshima d, graham d, shattuck l, rhodes ba. biological distribution of 99mtc-labeled yigsr and ikvav laminin peptides 246.

in rodents: 99mtc-ikvav peptide localizes to the lung. biochim biophys acta 1993; 1182: 197-204.

yamamoto m, yamamoto k, noumura t. type i collagen promotes modulation of cultured rabbit arterial smooth muscle cells from 247.

a contractile to a synthetic phenotype. exp cell res 1993; 204: 121-129.

tsilibary ec, reger la, vogel am, koliakos gg, anderson ss, charonis as, alegre jn, furcht lt. identification of a multifunctional, 248.

cell-binding peptide sequence from the a1(nc1) of type iv collagen. j cell biol 1990; 111: 1583-1591.

hocking dc, sottile j, mckeown-longo pj. activation of distinct a5b1-mediated signaling pathways by fibronectin’s cell adhesion 249.

and matrix assembly domains. j cell biol 1998; 141: 241-253.

alobaid n, salacinski hj, sales km, ramesh b, kannan ry, hamilton g, seifalian am. nanocomposite containing bioactive peptides 250.

promote endothelialisation by circulating progenitor cells: an in Vitro evaluation. eur j vasc endovasc surg 2006; 32: 76-83.

ferreira ls, gerecht s, fuller j, shieh hf, vunjak-novakovic g, langer r. bioactive hydrogel scaffolds for controllable vascular 251.

differentiation of human embryonic stem cells. biomaterials 2007; 28: 2706-2717.

grant ds, tashiro ki, segui-real b, yamada y, martin gr, kleinman hk. two different laminin domains mediate the differentiation 252.

of human endothelial cells into capillary-like structures in Vitro. cell 1989; 58: 933-943.

pollman mj, naumovski l, gibbons gh. vascular cell apoptosis: cell type specific modulation by transforming growth factor-β1 in 253.

endothelial cells Versus smooth muscle cells. circulation 1999; 99: 2019-2026.

zisch a, lutolf mp, hubbell ja. biopolymeric delivery matrices for angiogenic growth factors. cardiovasc pathol 2003; 12: 295-310.254.

pike d, cai s, pomraning k, firpo m, fisher r, shu x, prestwich g, peattie r. heparin-regulated release of growth factors 255. in Vitro and

angiogenic response in Vivo to implanted hyaluronan hydrogels containing vegf and bfgf. biomaterials 2006; 27: 5242-5251.

nillesen st, geutjes pj, wismans r, schalkwijk j, daamen wf, van kuppevelt th. increased angiogenesis and blood vessel maturation 256.

in acellular collagen-heparin scaffolds containing both fgf2 and vegf. biomaterials 2007; 28: 1123-1131.

gong y, he l, li j, zhou Q, ma z, gao c, shen j. hydrogel-filled polylactide porous scaffolds for cartilage tissue engineering. j biomed 257.

mater res b appl biomater 2007; 82: 192-204.

zisch ah, lutolf mp, ehrbar m, raeber gp, rizzi sc, davies n, schmokel h, bezuidenhout d, djonov vg, zilla p, hubbell ja. cell-258.

demanded release of vegf from synthetic, biointeractive cell-ingrowth matrices for vascularized tissue growth. the faseb journal

2003; 17: 2260-2262.

seliktar d, zisch ah, lutolf mp, wrana jl, hubbell ja. mmp-2 sensitive, vegf-bearing bioactive hydrogels for promotion of vascular 259.

healing. j biomed mater res a 2004; 68: 704-716.

herbrig k, pistrosch f, oelschlaegel u, wichmann g, wagner a, foerster s, richter s, gross p, passauer j. increased total number but 260.

impaired migratory activity and adhesion of endothelial progenitor cells in patients on long-term hemodialysis. am j kidney dis

2004; 44: 840-849.

vasa m, fichtlscherer s, aicher a, adler k, urbich c, martin h, zeiher a, dimmeler s. number and migratory activity of circulating 261.

endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. circ res 2001; 89: e1-7.

koshida r, rocic p, saito s, kiyooka t, zhang c, chilian wm. role of focal adhesion kinase in flow-induced dilation of coronary 219.

arterioles. arterioscler thromb vasc biol 2005; 25: 2548-2553.

malmstrom j, lindberg h, lindberg c, bratt c, wieslander e, delander el, sarnstrand b, burns js, mose-larsen p, fey s, marko-220.

varga g. transforming growth factor-b1 specifically induce proteins involved in the myofibroblast contractile apparatus. mol cell

proteomics 2004; 3: 466-477.

sinha s, hoofnagle mh, kingston pa, mccanna me, owens gk. transforming growth factor-b1 signaling contributes to development 221.

of smooth muscle cells from embryonic stem cells. am j physiol cell physiol 2004; 287: c1560-c1568.

hautmann mb, madsen cs, owens gk. a transforming growth factor beta (tgfb) control element drives tgfb-induced stimulation 222.

of smooth muscle a-actin gene expression in concert with two carg elements. j biol chem 1997; 272: 10948-10956.

li l, miano jm, mercer b, olson en. expression of the sm22a promoter in transgenic mice provides evidence for distinct transcriptional 223.

regulatory programs in vascular and visceral smooth muscle cells. j cell biol 1996; 132: 849-859.

zilberman a, dave v, miano jm, olson en, periasamy m. evolutionarily conserved promoter region containing carg-like elements is 224.

crucial for smooth muscle myosin heavy chain gene expression. circ res 1998; 82: 566-575.

olson en, perry m, schulz ra. regulation of muscle differentiation by the mef2 family of mads box transcription factors. dev biol 225.

1995; 172: 2-14.

benchabane h, wrana jl. gata- and smad1-dependent enhancers in the smad7 gene differentially interpret bone morphogenetic 226.

protein concentrations. mol cell biol 2003; 23: 6646-6661.

camoretti-mercado b, fernandes dj, dewundara s, churchill j, ma l, kogut pc, mcconville jf, parmacek ms, solway j. inhibition 227.

of transforming growth factor β-enhanced serum response factor-dependent transcription by smad7. j biol chem 2006; 281:

20383-20392.

nagai r, suzuki t, aizawa k, miyamoto s, amaki t, kawai-kowase k, sekiguchi ki, kurabayashi m. phenotypic modulation of vascular 228.

smooth muscle cells: dissection of transcriptional regulatory mechanisms. ann n y acad sci 2001; 947: 56-66.

rensen ss, doevendans pa, van eys gj. regulation and characteristics of vascular smooth muscle cell phenotypic diversity. neth 229.

heart j 2007; 15: 100-108.

chen cn, li ys, yeh yt, lee pl, usami s, chien s, chiu jj. synergistic roles of platelet-derived growth factor-bb and interleukin-1b in 230.

phenotypic modulation of human aortic smooth muscle cells. proc natl acad sci u s a 2006; 103: 2665-2670.

li x, van putten v, zarinetchi f, nicks me, thaler s, heasley le, nemenoff ra. suppression of smooth-muscle alpha-actin expression 231.

by platelet-derived growth factor in vascular smooth-muscle cells involves ras and cytosolic phospholipase a2. biochem j 1997;

327: 709-716.

hao h, ropraz p, verin v, camenzind e, geinoz a, pepper ms, gabbiani g, bochaton-piallat ml. heterogeneity of smooth muscle cell 232.

populations cultured from pig coronary artery. arterioscler thromb vasc biol 2002; 22: 1093-1099.

deguchi j, namba t, hamada h, nakaoka t, abe j, sato o, miyata t, makuuchi m, kurokawa k, takuwa y. targeting endogenous 233.

platelet-derived growth factor b-chain by adenovirus-mediated gene transfer potently inhibits in Vivo smooth muscle proliferation

after arterial injury. gene ther 1999; 6: 956-965.

miyata t, iizasa h, sai y, fujii j, terasaki t, nakashima e. platelet-derived growth factor-bb (pdgf-bb) induces differentiation of 234.

bone marrow endothelial progenitor cell-derived cell line tr-bme2 into mural cells, and changes the phenotype. j cell physiol

2005; 204: 948-955.

couet f, rajan n, mantovani d. macromolecular biomaterials for scaffold-based vascular tissue engineering. macromol biosci 2007; 235.

7: 701-718.

kannan ry, salacinski hj, butler pe, hamilton g, seifalian am. current status of prosthetic bypass grafts: a review. j biomed mater 236.

res b appl biomater 2005; 74: 570-581.

brody s, anilkumar t, liliensiek s, last ja, murphy cj, pandit a. characterizing nanoscale topography of the aortic heart valve 237.

basement membrane for tissue engineering heart valve scaffold design. tissue eng 2006; 12: 413-421.

lin yk, liu dc. studies of novel hyaluronic acid-collagen sponge materials composed of two different species of type i collagen. j 238.

biomater appl 2007; 21: 265-281.

shadwick re. mechanical design in arteries. j exp biol 1999; 202: 3305-3313.239.

appendices

218

references

219 App

duan hx, cheng lm, jian w, hu ls, lu gx. angiogenic potential difference between two types of endothelial progenitor cells from 283.

human umbilical cord blood. cell biol int 2006; 30: 1018-1027.

zhang r, yang h, li m, yao Q, chen c. acceleration of endothelial-like cell differentiation from cd14284. + monocytes in Vitro. exp

hematol 2005; 33: 1554-1563.

elsheikh e, uzunel m, he z, holgersson j, nowak g, sumitran-holgersson s. only a specific subset of human peripheral-blood 285.

monocytes has endothelial-like functional capacity. blood 2005; 106: 2347-2355.

sparmann a, bar-sagi d. ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. cancer cell 286.

2004; 6: 447-458.

anghelina m, moldovan l, zabuawala t, ostrowski mc, moldovan ni. a subpopulation of peritoneal macrophages form capillarylike 287.

lumens and branching patterns in Vitro. j cell mol med 2006; 10: 708-715.

charo i, taubman m. chemokines in the pathogenesis of vascular disease. circ res 2004; 95: 858-866.288.

kuroda t, kitadai y, tanaka s, yang x, mukaida n, yoshihara m, chayama k. monocyte chemoattractant protein-1 transfection 289.

induces angiogenesis and tumorigenesis of gastric carcinoma in nude mice via macrophage recruitment. clin cancer res 2005;

11: 7629-7636.

hong k, ryu j, han k. monocyte chemoattractant protein-1-induced angiogenesis is mediated by vascular endothelial growth 290.

factor-a. blood 2005; 105: 1405-1407.

niiyama h, kai h, yamamoto t, shimada t, sasaki k, murohara t, egashira k, imaizumi t. roles of endogenous monocyte 291.

chemoattractant protein-1 in ischemia-induced neovascularization. j am coll cardiol 2004; 44: 661-666.

yamada m, kim s, egashira k, takeya m, ikeda t, mimura o, iwao h. molecular mechanism and role of endothelial monocyte 292.

chemoattractant protein-1 induction by vascular endothelial growth factor. arterioscler thromb vasc biol 2003; 23: 1996-2001.

li a, varney m, valasek j, godfrey m, dave b, singh r. autocrine role of interleukin-8 in induction of endothelial cell proliferation, 293.

survival, migration and mmp-2 production and angiogenesis. angiogenesis 2005; 8: 63-71.

cai l, johnstone bh, cook tg, liang z, traktuev d, cornetta k, ingram da, rosen ed, march kl. suppression of hepatocyte growth 294.

factor production impairs the ability of adipose-derived stem cells to promote ischemic tissue revascularization. stem cells 2007;

25: 3234-3243.

bordoni v, alonzi t, zanetta l, khouri d, conti a, corazzari m, bertolini f, antoniotti p, pisani g, tognoli f, dejana e, tripodi m. 295.

hepatocyte-conditioned medium sustains endothelial differentiation of human hematopoietic-endothelial progenitors.

hepatology 2007; 45: 1218-1228.

asahara t, masuda h, takahashi t, kalka c, pastore c, silver m, kearne m, magner m, isner jm. bone marrow origin of endothelial 296.

progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. circ res 1999; 85:

221-228.

losordo dw, schatz ra, white cj, udelson je, veereshwarayya v, durgin m, poh kk, weinstein r, kearney m, chaudhry m, burg 297.

a, eaton l, heyd l, thorne t, shturman l, hoffmeister p, story k, zak v, dowling d, traverse jh, olson re, flanagan j, sodano d,

murayama t, kawamoto a, kusano kf, wollins j, welt f, shah p, soukas p, asahara t, henry td. intramyocardial transplantation of

autologous cd34+ stem cells for intractable angina: a phase i/iia double-blind, randomized controlled trial. circulation 2007; 115:

3165-3172.

schachinger v, assmus b, britten mb, honold j, lehmann r, teupe c, abolmaali nd, vogl tj, hofmann wk, martin h, dimmeler 298.

s, zeiher am. transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year

results of the topcare-ami trial. j am coll cardiol 2004; 44: 1690-1699.

leor j, rozen l, zuloff-shani a, feinberg ms, amsalem y, barbash im, kachel e, holbova r, mardor y, daniels d, ocherashvilli a, 299.

orenstein a, danon d. ex vivo activated human macrophages improve healing, remodeling, and function of the infarcted heart.

circulation 2006; 114: i94-100.

urbich c, heeschen c, aicher a, dernbach e. relevance of monocytic features for neovascularization capacity of circulating 300.

endothelial progenitor cells. circulation 2003; 108: 2511-2516.

kinnaird t, stabile e, burnett ms, lee cw, barr s, fuchs s, epstein se. marrow-derived stromal cells express genes encoding a broad 262.

spectrum of arteriogenic cytokines and promote in Vitro and in Vivo arteriogenesis through paracrine mechanisms. circ res 2004;

94: 678-685.

gnecchi m, zhang z, ni a, dzau vj. paracrine mechanisms in adult stem cell signaling and therapy. circ res 2008; 103: 1204-1219.263.

takahashi m, li ts, suzuki r, kobayashi t, ito h, ikeda y, matsuzaki m, hamano k. cytokines produced by bone marrow cells can 264.

contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury. ajp - heart and

circulatory physiology 2006; 291: h886-h893.

hristov m, erl w, weber p. endothelial progenitor cells: mobilization, differentiation, and homing. arterioscler thromb vasc biol 265.

2003; 23: 1185-1189.

jackson k, majka s, wang h, pocius j, hartley c, majesky mw, entman m, michael lh, hirschi kk, goodell m. regeneration of ischemic 266.

cardiac muscle and vascular endothelium by adult stem cells. j clin invest 2001; 107: 1395-1402.

ma n, stamm c, kaminski a, li w, kleine hd, muller-hilke b, zhang l, ladilov y, egger d, steinhoff g. human cord blood cells induce 267.

angiogenesis following myocardial infarction in nod/scid-mice. cardiovasc res 2005; 66: 45-54.

van der strate bwa, popa er, schipper m, brouwer la, hendriks m, harmsen mc, van luyn mja. circulating human cd34268. + progenitor

cells modulate neovascularization and inflammation in a nude mouse model. j mol cell cardiol 2007; 42: 1086-1097.

van amerongen mj, bou-gharios g, popa er, van aj, petersen ah, van dg, van lm, harmsen mc. bone marrow-derived myofibroblasts 269.

contribute functionally to scar formation after myocardial infarction. j pathol 2007; 214: 377-386.

van amerongen mj, harmsen mc, van rn, petersen ah, van luyn mja. macrophage depletion impairs wound healing and increases 270.

left ventricular remodeling after myocardial injury in mice. am j pathol 2007; 170: 818-829.

anghelina m, krishnan p, moldovan l, moldovan n. monocytes and macrophages form branched cell columns in matrigel: 271.

implications for a role in neovascularization. stem cells dev 2004; 13: 665-676.

harraz m, jiao c, hanlon hd. cd34- blood derived human endothelial cell progenitors. stem cells 2001; 19: 304-312.272.

sharifi bg, zeng z, wang l, song l, chen h, Qin m, sierra-honigmann mr, wachsmann-hogiu s, shah pk. pleiotrophin induces 273.

transdifferentiation of monocytes into functional endothelial cells. arterioscler thromb vasc biol 2006; 26: 1273-1280.

ziegelhoeffer t, fernandez b, kostin s, heil m, voswinckel r, helisch a, schaper w. bone marrow-derived cells do not incorporate 274.

into the adult growing vasculature. circ res 2004; 94: 230-238.

bautz f, rafii s, kanz l, mohle r. expression and secretion of vascular endothelial growth factor-a by cytokine-stimulated 275.

hematopoietic progenitor cells: possible role in the hematopoietic microenvironment. exp hematol 2000; 28: 700-706.

majka m, janowska-wieczorek a, ratajczak j, ehrenman k, pietrzkowski z, kowalska ma, gewirtz am, emerson sg, ratajczak 276.

mz. numerous growth factors, cytokines, and chemokines are secreted by human cd34+ cells, myeloblasts, erythroblasts, and

megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner. blood 2001; 97: 3075-3085.

bonello l, basire a, sabatier f, paganelli f, dignat-george f. endothelial injury induced by coronary angioplasty triggers mobilization 277.

of endothelial progenitor cells in patients with stable coronary artery disease. j thromb haemost 2006; 4: 979-981.

susen s, sautiere k, mouquet f, cuilleret f, chmait a, mcfadden ep, hennache b, richard f, de groote p, lablanche jm, dallongeville 278.

j, bauters c, jude b, van belle e. serum hepatocyte growth factor levels predict long-term clinical outcome after percutaneous

coronary revascularization. eur heart j 2005; 26: 2387-2395.

woywodt a, erdbruegger u, haubitz m. circulating endothelial cells and endothelial progenitor cells after angioplasty: news from 279.

the endothelial rescue squad. j thromb haemost 2006; 4: 976-978.

rohde e, bartmann c, schallmoser k, reinisch a, lanzer g, linkesch w, guelly c, strunk d. immune cells mimic the morphology of 280.

endothelial progenitor colonies In Vitro. stem cells 2007; 25: 1746-1752.

moldovan ni, goldschmidt-clermont pj, parker-thornburg j, shapiro sd, kolattukudy pe. contribution of monocytes/macrophages 281.

to compensatory neovascularization - the drilling of metalloelastase-positive tunnels in ischemic myocardium. circ res 2000; 87:

378-384.

anghelina m, krishnan p, moldovan l, moldovan n. monocytes/macrophages cooperate with progenitor cells during 282.

neovascularization and tissue repair: conversion of cell columns into fibrovascular bundles. am j pathol 2006; 168: 529-541.

appendices

220

references

221 App

jolicoeur em, granger cb, fakunding jl, mockrin sc, grant sm, ellis sg, weisel rd, goodell ma. bringing cardiovascular cell-based 323.

therapy to clinical application: perspectives based on a national heart, lung, and blood institute cell therapy working group

meeting. am heart j 2007; 153: 732-742.

perin ec, dohmann hf, borojevic r, silva sa, sousa al, silva gv, mesquita ct, belem l, vaughn wk, rangel fo, assad ja, carvalho ac, 324.

branco rv, rossi mi, dohmann hj, willerson jt. improved exercise capacity and ischemia 6 and 12 months after transendocardial

injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. circulation 2004; 110: ii213-ii218.

beeres sl, lamb hj, roes sd, holman er, kaandorp ta, fibbe we, de ra, van der wall ee, schalij mj, bax jj, atsma de. effect of 325.

intramyocardial bone marrow cell injection on diastolic function in patients with chronic myocardial ischemia. j magn reson

imaging 2008; 27: 992-997.

vandervelde s, van luyn mja, rosenbaum mh, petersen ah, tio ra, harmsen mc. stem cell-related cardiac gene expression early 326.

after murine myocardial infarction. cardiovasc res 2006.

wiener cm, booth g, semenza gl. 327. In Vivo expression of mrnas encoding hypoxia-inducible factor 1. biochem biophys res commun

1996; 225: 485-488.

huang le, gu j, schau m, bunn hf. regulation of hypoxia-inducible factor 1alpha is mediated by an o2-dependent degradation 328.

domain via the ubiquitin-proteasome pathway. proc natl acad sci u s a 1998; 95: 7987-7992.

asahara t, takahashi t, masuda h, kalka c, chen d, iwaguro h, inai y, silver m, isner jm. vegf contributes to postnatal 329.

neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. embo j 1999; 18: 3964-3972.

grunewald m, avraham i, dor y, bachar-lustig e, itin a, yung s, chimenti s, landsman l, abramovitch r, keshet e. vegf-induced 330.

adult neovascularization: recruitment, retention, and role of accessory cells. cell 2006; 124: 175-189.

morimoto h, takahashi m, shiba y, izawa a, ise h, hongo m, hatake k, motoyoshi k, ikeda u. bone marrow-derived cxcr4331. + cells

mobilized by macrophage colony-stimulating factor participate in the reduction of infarct area and improvement of cardiac

remodeling after myocardial infarction in mice. am j pathol 2007; 171: 755-766.

yamaguchi j, kusano kf, masuo o, kawamoto a, silver m, murasawa s, bosch-marce m, masuda h, losordo dw, isner jm, asahara t. 332.

stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization.

circulation 2003; 107: 1322-1328.

capoccia bj, gregory ad, link dc. recruitment of the inflammatory subset of monocytes to sites of ischemia induces angiogenesis 333.

in a monocyte chemoattractant protein-1-dependent fashion. j leukoc biol 2008; 84: 760-768.

hattori k, dias s, heissig b, hackett n, lyden d, tateno m, hicklin d, zhu z, witte l, crystal r, moore ma, rafii s. vascular endothelial 334.

growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem

cells. j exp med 2001; 193: 1005-1014.

heeschen c, aicher a, lehmann r, fichtlscherer s, vasa m, urbich c, mildner-rihm c, martin h, zeiher am, dimmeler s. erythropoietin 335.

is a potent physiologic stimulus for endothelial progenitor cell mobilization. blood 2003; 102: 1340-1346.

wallez y, huber p. endothelial adherens and tight junctions in vascular homeostasis, inflammation and angiogenesis. biochimica 336.

et biophysica acta (bba) - biomembranes 2008; 1778: 794-809.

gavard j, gutkind js. vegf controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of ve-337.

cadherin. nat cell biol 2006; 8: 1223-1234.

hirase t, kawashima s, wong ey, ueyama t, rikitake y, tsukita s, yokoyama m, staddon jm. regulation of tight junction permeability 338.

and occludin phosphorylation by rhoa-p160rock-dependent and -independent mechanisms. j biol chem 2001; 276: 10423-10431.

stamatovic sm, dimitrijevic ob, keep rf, andjelkovic av. protein kinase calpha-rhoa cross-talk in ccl2-induced alterations in brain 339.

endothelial permeability. j biol chem 2006; 281: 8379-8388.

peled a, zipori d, abramsky o, ovadia h, shezen e. expression of alpha-smooth muscle actin in murine bone marrow stromal cells. 340.

blood 1991; 78: 304-309.

peled a, kollet o, ponomaryov t, petit i, franitza s, grabovsky v, slav mm, nagler a, lider o, alon r, zipori d, lapidot t. the chemokine 341.

sdf-1 activates the integrins lfa-1, vla-4, and vla-5 on immature human cd34+ cells: role in transendothelial/stromal migration

and engraftment of nod/scid mice. blood 2000; 95: 3289-3296.

sengupta s, sellers l, li r, gherardi e, zhao g, watson n, sasisekharan r, fan t. targeting of mitogen-activated protein kinases 301.

and phosphatidylinositol 3 kinase inhibits hepatocyte growth factor/scatter factor-induced angiogenesis. circulation 2003; 107:

2955-2961.

tomita n, morishita r, taniyama y, koike h, aoki m, shimizu h, matsumoto k, nakamura t, kaneda y, ogihara t. angiogenic property 302.

of hepatocyte growth factor is dependent on upregulation of essential transcription factor for angiogenesis, ets-1. circulation

2003; 107: 1411-1417.

nian m, lee p, khaper n, liu p. inflammatory cytokines and postmyocardial infarction remodeling. circ res 2004; 94: 1543-1553.303.

vandervelde s, van amerongen mj, tio ra, petersen ah, van luyn mja, harmsen mc. increased inflammatory response and 304.

neovascularization in reperfused vs. non-reperfused murine myocardial infarction. cardiovasc pathol 2006; 15: 83-90.

kocher aa, schuster md, szabolcs mj, takuma s, burkhoff d, wang j, homma s, edwards nm, itescu s. neovascularization of ischemic 305.

myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves

cardiac function. nat med 2001; 7: 430-436.

shiojima i, sato k, izumiya y, schiekofer s, ito m, liao r, colucci ws, walsh k. disruption of coordinated cardiac hypertrophy and 306.

angiogenesis contributes to the transition to heart failure. j clin invest 2005; 115: 2108-2118.

risau w. mechanisms of angiogenesis. nature 1997; 386: 671-674.307.

distler jh, hirth a, kurowska-stolarska m, gay re, gay s, distler o. angiogenic and angiostatic factors in the molecular control of 308.

angiogenesis. Q j nucl med 2003; 47: 149-161.

murohara t, ikeda h, duan j, shintani s, sasaki k, eguchi h, onitsuka i, matsui k, imaizumi t. transplanted cord blood-derived 309.

endothelial precursor cells augment postnatal neovascularization. j clin invest 2000; 105: 1527-1536.

cottler-fox mh, lapidot t, petit i, kollet o, dipersio jf, link d, devine s. stem cell mobilization. hematology am soc hematol educ 310.

program 2003; 419-437.

hattori k, heissig b, rafii s. the regulation of hematopoietic stem cell and progenitor mobilization by chemokine sdf-1. leuk 311.

lymphoma 2003; 44: 575-582.

jujo k, ii m, losordo dw. endothelial progenitor cells in neovascularization of infarcted myocardium. j mol cell cardiol 2008; 45: 312.

530-544.

jevon m, dorling a, hornick pi. progenitor cells and vascular disease. cell prolif 2008; 41 suppl 1: 146-164.313.

ward mr, stewart dj, kutryk mj. endothelial progenitor cell therapy for the treatment of coronary disease, acute mi, and pulmonary 314.

arterial hypertension: current perspectives. catheter cardiovasc interv 2007; 70: 983-998.

schatteman gc, awad a. 315. In Vivo and in Vitro properties of cd34+ and cd14+ endothelial cell precursors. adv exp med biol 2003; 522:

9-16.

schatteman gc, dunnwald m, jiao c. biology of bone marrow-derived endothelial cell precursors. ajp - heart and circulatory 316.

physiology 2007; 292: h1-18.

zhang sj, zhang h, hou m, zheng z, zhou j, su w, wei y, hu ss. is it possible to obtain true endothelial progenitor cells by 317. in Vitro

culture of bone marrow mononuclear cells? stem cells dev 2007; 16: 683-690.

fan cl, li y, gao pj, liu jj, zhang xj, zhu dl. differentiation of endothelial progenitor cells from human umbilical cord blood cd34318. +

cells in Vitro. acta pharmacol sin 2003; 24: 212-218.

nagano m, yamashita t, hamada h, ohneda k, kimura k, nakagawa t, shibuya m, yoshikawa h, ohneda o. identification of 319.

functional endothelial progenitor cells suitable for the treatment of ischemic tissue using human umbilical cord blood. blood

2007; 110: 151-160.

werner n, junk s, laufs u, link a, walenta k, bohm m, nickenig g. intravenous transfusion of endothelial progenitor cells reduces 320.

neointima formation after vascular injury. circ res 2003; 93: e17-e24.

zhang w, zhang g, jin h, hu r. characteristics of bone marrow-derived endothelial progenitor cells in aged mice. biochem biophys 321.

res commun 2006; 348: 1018-1023.

pompilio g, capogrossi mc, pesce m, alamanni f, dicampli c, achilli f, germani a, biglioli p. endothelial progenitor cells and 322.

cardiovascular homeostasis: clinical implications. international journal of cardiology 2009; 131: 156-167.

appendices

222

references

223 App

sarkar s, sales km, hamilton g, seifalian am. addressing thrombogenicity in vascular graft construction. j biomed mater res b appl 364.

biomater 2007; 82: 100-108.

plate g, hollier lh, gloviczki p, dewanjee mk, kaye mp. overcoming failure of venous vascular prostheses. surgery 1984; 96: 365.

503-510.

atluri p, woo yj. pro-angiogenic cytokines as cardiovascular therapeutics: assessing the potential. biodrugs 2008; 22: 209-222.366.

dardik a, liu a, ballermann bj. chronic 367. in Vitro shear stress stimulates endothelial cell retention on prosthetic vascular grafts and

reduces subsequent in Vivo neointimal thickness. j vasc surg 1999; 29: 157-167.

urbich c, aicher a, heeschen c, dernbach e, hofmann w, zeiher a, dimmeler s. soluble factors released by endothelial progenitor 368.

cells promote migration of endothelial cells and cardiac resident progenitor cells. j mol cell cardiol 2005; 39: 733-742.

armstrong ej, bischoff j. heart valve development: endothelial cell signaling and differentiation. circ res 2004; 95: 459-470.369.

tanaka t, saika s, ohnishi y, ooshima a, mcavoy jw, liu cy, azhar m, doetschman t, kao ww. fibroblast growth factor 2: roles of 370.

regulation of lens cell proliferation and epithelial-mesenchymal transition in response to injury. mol vis 2004; 10: 462-467.

arciniegas e, neves yc, carrillo lm. potential role for insulin-like growth factor ii and vitronectin in the endothelial-mesenchymal 371.

transition process. differentiation 2006; 74: 277-292.

kilian o, flesch i, wenisch s, taborski b, jork a, schnettler r, jonuleit t. effects of platelet growth factors on human mesenchymal 372.

stem cells and human endothelial cells in Vitro. eur j med res 2004; 9: 337-344.

hyman km, seghezzi g, pintucci g, stellari g, kim jh, grossi ea, galloway ac, mignatti p. transforming growth factor-b1 induces 373.

apoptosis in vascular endothelial cells by activation of mitogen-activated protein kinase. surgery 2002; 132: 173-179.

ahmadi h, baharvand h, ashtiani sk, soleimani m, sadeghian h, ardekani jm, mehrjerdi nz, kouhkan a, namiri m, madani-civi 374.

m, fattahi f, shahverdi a, dizaji av. safety analysis and improved cardiac function following local autologous transplantation of

cd133+ enriched bone marrow cells after myocardial infarction. curr neurovasc res 2007; 4: 153-160.

meyer gp, wollert kc, lotz j, steffens j, lippolt p, fichtner s, hecker h, schaefer a, arseniev l, hertenstein b, ganser a, drexler 375.

h. intracoronary bone marrow cell transfer after myocardial infarction: eighteen months’ follow-up data from the randomized,

controlled boost (bone marrow transfer to enhance st-elevation infarct regeneration) trial. circulation 2006; 113: 1287-1294.

wollert kc, meyer gp, lotz j, ringes lichtenberg s, lippolt p, breidenbach c, fichtner s, korte t, hornig b, messinger d, arseniev l, 376.

hertenstein b, ganser a, drexler h. intracoronary autologous bone-marrow cell transfer after myocardial infarction: the boost

randomised controlled clinical trial. the lancet 2004; 364: 141-148.

hirsch a, nijveldt r, van d, v, biemond bj, doevendans pa, van rossum ac, tijssen jg, zijlstra f, piek jj. intracoronary infusion 377.

of autologous mononuclear bone marrow cells or peripheral mononuclear blood cells after primary percutaneous coronary

intervention: rationale and design of the hebe trial--a prospective, multicenter, randomized trial. am heart j 2006; 152: 434-441.

hirsch a, nijveldt r, van d, v, tio ra, van der giessen wj, marques km, doevendans pa, waltenberger j, ten berg jm, aengevaeren 378.

wr, biemond bj, tijssen jg, van rossum ac, piek jj, zijlstra f. intracoronary infusion of autologous mononuclear bone marrow cells

in patients with acute myocardial infarction treated with primary pci: pilot study of the multicenter hebe trial. catheter cardiovasc

interv 2008; 71: 273-281.

schachinger v, erbs s, elsasser a, haberbosch w, hambrecht r, holschermann h, yu j, corti r, mathey dg, hamm cw, suselbeck 379.

t, werner n, haase j, neuzner j, germing a, mark b, assmus b, tonn t, dimmeler s, zeiher am, for the repair-ami investigators.

improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial

infarction: final 1-year results of the repair-ami trial. eur heart j 2006; 27: 2775-2783.

erbs s, linke a, schachinger v, assmus b, thiele h, diederich kw, hoffmann c, dimmeler s, tonn t, hambrecht r, zeiher am, schuler 380.

g. restoration of microvascular function in the infarct-related artery by intracoronary transplantation of bone marrow progenitor

cells in patients with acute myocardial infarction: the doppler substudy of the reinfusion of enriched progenitor cells and infarct

remodeling in acute myocardial infarction (repair-ami) trial. circulation 2007; 116: 366-374.

assmus b, schachinger v, teupe c, britten m, lehmann r, dobert n, grunwald f, aicher a, urbich c, martin h, hoelzer d, dimmeler 381.

s, zeiher a. transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (topcare-ami).

circulation 2002; 106: 3009-3017.

voermans c, rood pml, hordijk pl, gerritsen wr, van der schoot ce. adhesion molecules involved in transendothelial migration of 342.

human hematopoietic progenitor cells. stem cells 2000; 18: 435-443.

smadja dm, bieche i, silvestre js, germain s, cornet a, laurendeau i, duong-van huyen jp, emmerich j, vidaud m, aiach m, gaussem 343.

p. bone morphogenetic proteins 2 and 4 are selectively expressed by late outgrowth endothelial progenitor cells and promote

neoangiogenesis. arterioscler thromb vasc biol 2008; 28: 2137-2143.

sieveking dp, buckle a, celermajer ds, ng mkc. strikingly different angiogenic properties of endothelial progenitor cell 344.

subpopulations: insights from a novel human angiogenesis assay. j am coll cardiol 2008; 51: 660-668.

van belle e, witzenbichler b, chen d, silver m, chang l, schwall r, isner jm. potentiated angiogenic effect of scatter factor/345.

hepatocyte growth factor via induction of vascular endothelial growth factor: the case for paracrine amplification of angiogenesis.

circulation 1998; 97: 381-390.

khoo cp, pozzilli p, alison mr. endothelial progenitor cells and their potential therapeutic applications. regen med 2008; 3: 346.

863-876.

symes jf, vale pr, schatz ra, losordo dw. clinical trials of myocardial vegf gene transfer. gene therapy and regulation 2001; 1: 347.

311-323.

chen rr, silva ea, yuen ww, brock aa, fischbach c, lin as, guldberg re, mooney dj. integrated approach to designing growth 348.

factor delivery systems. faseb j 2007; 21: 3896-3903.

jain rk, duda dg, clark jw, loeffler js. lessons from phase iii clinical trials on anti-vegf therapy for cancer. nat clin pract oncol 349.

2006; 3: 24-40.

hao x, silva ea, mansson-broberg a, grinnemo kh, siddiqui aj, dellgren g, wardell e, brodin la, mooney dj, sylven c. angiogenic 350.

effects of sequential release of vegf-a165 and pdgf-bb with alginate hydrogels after myocardial infarction. cardiovasc res 2007;

75: 178-185.

roy r, zhang b, moses ma. making the cut: protease-mediated regulation of angiogenesis. exp cell res 2006; 312: 608-622.351.

richardson tp, peters mc, ennett ab, mooney dj. polymeric system for dual growth factor delivery. nat biotechnol 2001; 19: 352.

1029-1034.

ehrbar m, djonov vg, schnell c, tschanz sa, martiny-baron g, schenk u, wood j, burri ph, hubbell ja, zisch ah. cell-demanded 353.

liberation of vegf121 from fibrin implants induces local and controlled blood vessel growth. circ res 2004; 94: 1124-1132.

herbrig k, gebler k, oelschlaegel u, pistrosch f, foerster s, wagner a, gross p, passauer j. kidney transplantation substantially 354.

improves endothelial progenitor cell dysfunction in patients with end-stage renal disease. am j transplant 2006; 6: 2922-2928.

kränkel n, katare rg, siragusa m, barcelos ls, campagnolo p, mangialardi g, fortunato o, spinetti g, tran n, zacharowski k, 355.

wojakowski w, mroz i, herman a, manning fox je, macdonald pe, schanstra jp, bascands jl, ascione r, angelini g, emanueli c,

madeddu p. role of kinin b2 receptor signaling in the recruitment of circulating progenitor cells with neovascularization potential.

circ res 2008; 103: 1335-1343.

langer r, vacanti jp. tissue engineering. science 1993; 260: 920-926.356.

hristov m, weber c. endothelial progenitor cells in vascular repair and remodeling. pharmacol res 2008; 58: 148-151.357.

deb a, skelding k, wang s, reeder m, simper d, caplice n. integrin profile and 358. In Vivo homing of human smooth muscle progenitor

cells. circulation 2004; 110: 2673-2677.

sata m, saiura a, kunisato a, tojo a, okada sy, tokuhisa t, hirai h, makuuchi m, hirata y, nagai r. hematopoietic stem cells 359.

differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. nat med 2002; 8: 403-409.

asahara t. cell therapy and gene therapy using endothelial progenitor cells for vascular regeneration. handb exp pharmacol 2007; 360.

180: 181-194.

kawamoto a, tkebuchava t, yamaguchi ji, nishimura h, yoon ys, milliken c, uchida s, masuo o, iwaguro h, ma h, hanley a, silver 361.

m, kearney m, losordo dw, isner jm, asahara t. intramyocardial transplantation of autologous endothelial progenitor cells for

therapeutic neovascularization of myocardial ischemia. circulation 2003; 107: 461-468.

gottrup f. oxygen in wound healing and infection. world journal of surgery 2004; 28: 312-315.362.

moossavi s, tuttle ab, vachharajani tj, plonk g, bettmann ma, majekodunmi o, russell gb, regan jd, freedman bi. long-term 363.

outcomes of transposed basilic vein arteriovenous fistulae. hemodial int 2008; 12: 80-84.

appendices

224

tateishi-yuyama e, matsubara h, murohara t, ikeda u, shintani s, masaki h, amano k, kishimoto y, yoshimoto k, akashi h, shimada 382.

k, iwasaka t, imaizumi t. therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-

marrow cells: a pilot study and a randomised controlled trial. lancet 2002; 360: 427-435.

van huyen jp, smadja dm, bruneval p, gaussem p, dal-cortivo l, julia p, fiessinger jn, cavazzana-calvo m, aiach m, emmerich j. 383.

bone marrow-derived mononuclear cell therapy induces distal angiogenesis after local injection in critical leg ischemia. mod

pathol 2008; 21: 837-846.

zhang h, zhang n, li m, feng h, jin w, zhao h, chen x, tian l. therapeutic angiogenesis of bone marrow mononuclear cells (mncs) 384.

and peripheral blood mncs: transplantation for ischemic hindlimb. ann vasc surg 2008; 22: 238-247.

ott i, keller u, knoedler m, gotze ks, doss k, fischer p, urlbauer k, debus g, von bn, rudelius m, schomig a, peschel c, oostendorp 385.

ra. endothelial-like cells expanded from cd34+ blood cells improve left ventricular function after experimental myocardial

infarction. faseb j 2005; 19: 992-994.

sondergaard cs, bonde j, degnæs-hansen f, nielsen jm, zachar v, holm m, hokland p, pedersen l. minimal engraftment of human 386.

cd34+ cells mobilized from healthy donors in the infarcted heart of athymic nude rats. stem cells dev 2008.

koponen jk, kekarainen t, heinonen e, laitinen a, nystedt j, laine j, yla-herttuala s. umbilical cord blood-derived progenitor cells 387.

enhance muscle regeneration in mouse hindlimb ischemia model. mol ther 2007; 15: 2172-2177.

contents chapter 09 - University of Groningen · and erythropoietin [335], amongst others, which...

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