ANGIOGENESIS

Presented By

Name : Dibyendu DuttaM. Pharm, Pharmacology, 1st Year, 1st SemesterNSHM KNOWLEDGE CAMPUS, KOLKATAGROUP OF INSTITUTIONS

INTRODUCTION

The word “Angio” means blood vessels while “genesis” means creation, i.e. Angiogenesis is the formation of new blood vessels from pre-existing vessels.

Angiogenesis is a normal process in growth and development, as well as in wound healing.

Angiogenesis mainly occurs by two ways: 1. Sprouting angiogensis 2. Intussusceptive angiogenesis

SPROUTING ANGIOGENESISIt occurs in several well-characterized stages:

1. Activation of VEGF receptors of endothelial cells present in pre-existing veins.

2. The activated endothelial cells escape from the original vessel walls by help of protease.

3. Proliferation of endothelial cells into the surrounding matrix.4. Migration of endothelial towards the source of the angiogenic stimulus5. Re-organisation of endothelial cells to form tubules with a central lumen &

interconnection of new tubules to form a branched network.

INTUSSUSCEPTIVE ANGIOGENESIS Intussusceptive, also known as Splitting angiogenesis i.e. a single vessel split in

two. There are four phases of intussusceptive angiogenesis.

1. Two opposing capillary walls establish a zone of contact. 2. Perforation of vessel bilayer to allow growth factors and cells to penetrate into the

lumen. 3. Formation of a core at the zone of contact between two vessels & is filled with

pericytes and myofibroblasts. 4. The core is fleshed out with no alterations to the basic structure.

STIMULATORS OF ANGIOGENESIS

Basic fibroblast growth factor (bFGF)

Vascular endothelial growth factor (VEGF)

Angiogenin

Epidermal growth factor

Interleukin 8

Granulocyte colony stimulating factor

Placental growth factor

Platelet-derived endothelial growth factor

Tumor necrosis factor alpha (TNF-α)

INHIBITORS OF ANGIOGENESIS

Naturally occurring angiogenic inhibitors

Thrombospondin, Interferon, Metalloproteinase inhbitors

Tumor derived inhibitors Angiostatin, Endostatin

Pharmacological inhibitors Thalidomide, Carboxyamidotriazole (CAI)

Synthetic inhibitors Synthetic Protease Inhibitors, Anti-adhesive Peptides [3]

PHYSIOLOGICAL ANGIOGENESIS

Some of the normal situations where angiogenesis is important include:• Wound healing.• Formation of Placenta during Pregnancy.• Regeneration of endometrium after menstruation.• Heart attack: New coronary vessels could repair damaged heart.• Neurodegenarative ills: An increased blood supply could minimize neuronal

damage in brain.• Angiogenesis can bypass the blood clots in legs and improve circulation.

Angiogenesis in uterine lining

Angiogenesis in tissue during wound healing

PATHOLOGICAL ANGIOGENESIS

The imbalance between the angiogenic factors & the anti-angiogenic agents can cause several complications, such as:

THE SWITCH OFF & SWITCH ON EFFECT

When tumor tissues require fuel (nutrients and oxygen), angiogenesis is stimulated.

The switch to the angiogenic phenotype involves a change in the local equilibrium between positive and negative regulators of angiogenesis.

CANCER TREATMENT WITH ANTI-ANGIOGENIC AGENTS

For the metastatic spread of cancer tissue, growth of vascular network is important.

Angiogenesis plays the vital role in this step by providing nutrients & oxygen.

Angiogenesis is regulated by both activator & inhibitor molecules.

The imbalance between positive & negative regulator of angiogenesis produces a signal.

The signaling initiates certain genes that make proteins which promotes the growth of blood vessels.

Continued…

The scientists are studying on natural & synthetic angiogenic inhibitors to prevent or slow the growth of cancer.

Cytotoxic chemotherapy suppresses the cancer directly.

The anti-angiogenic therapy suppress it indirectly by depriving the cells of nutrients & oxygen.

Thus the combination of chemotherapy along with anti-angiogenic therapy might be beneficial for the treatment of cancer.

Continued… For example, bevacizumab (Avastin®) is a monoclonal antibody, that

binds to VEGF receptors.

Avastin is designed to directly bind to VEGF extracellularly to prevent interaction with VEGF receptors (VEGFRs) on the surface of endothelial cells, and thereby may inhibit VEGF's angiogenic activity

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