Placental structure and function in fetal growth restriction and stillbirth
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PL4.3. THE EFFECT OF MATERNAL DIABETES ON FETO-PLACENTAL ENDOTHELIAL CELLS Ursula Hiden a , Silvija Cvitic a, b , Francisca Diaz a , Evelyn Jantscher- Krenn a , Gernot Desoye a a Department of Obstetrics and Gynecology, Medical Univeristy of Graz, Graz, Austria; b Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria Gestational diabetes mellitus (GDM) is one of the most frequent preg- nancy pathologies. As other types of diabetes and resulting from the obesity epidemic, GDM is a growing problem worldwide. Even by women under good glycaemic control, the maternal diabetic environment causes metabolic derangements in the fetus. Thus, the fetal environment is characterized by hyperglycaemia, hyperinsulinemia, metabolically- induced hypoxia and altered levels of growth factors which affect placental and fetal development. Histological studies revealed hyper- vascularisation and reduced endothelial expression of cell junction mol- ecules in the placenta. Furthermore, placental vessels show altered response to vaso-relaxing agents. These findings indicate changes in placental endothelial functions as a consequence of the diabetic envi- ronment in utero. The human placenta is a rich source of primary feto-placental endothelial cells and thus gives a great opportunity to investigate endothelial changes occurring in pregnancy pathologies such as GDM. These primary feto- placental endothelial cells are well characterized and maintain their phenotype in vitro. Using these human primary feto-placental endothelial cells, we revealed that the intrauterine diabetic environment indeed causes sustainable functional changes in placental endothelial cells. These changes are rep- resented by altered angiogenesis, proliferation and gene expression. We speculate that the endothelial cell phenotype in GDM contributes to altered placental function and may even reflect changes in the fetuses of diabetic mothers. PL5.1. UTERO-PLACENTAL VASCULARIZATION DURING THE FIRST TRIMESTER: WHAT ARE THE NON-INVASIVE IMAGING TOOLS IN 2014? Olivier Morel a, b , Anne-Claire Chabot-Lecoanet a, b , Jie Duan a,b , Estelle Perdiolle-Galet a, b a Regional Maternity of University, Nancy, France; b IADI Inserm U947, Nancy, France Introduction: The physiopathology of utero-placental (UP) vasculariza- tion development is still partially unknown. Major progresses have been achieved, such as the description of the myometrial vascular shunt. Major endpoints, however, such as the perfusion timing of intervillous space by maternal blood, remain unclear. This review aimed to evaluate available non-invasive imaging techniques of UP vascularization during the first trimester. Methods: literature review from Medline. Results: Until recently, 2D Doppler examination was the reference. How- ever, its poor predictive values make it unusable in clinical practice. 3D Doppler angiography (3DPD), more sensitive to slow flow, now allows to quantify flows directly into the UP unit. The predictive value of this test for the prediction of preeclampsia (PE) and intrauterine growth restriction (IUGR) seems high. However, this technique has two major drawbacks: its dependence on machine settings and the lack of information as to the direction of flow, which makes it impossible to disentangle maternal and fetal flow. Performance could be improved by contrast agents. New MRI sequences (BOLD) seem to allow an early diagnosis of IUGR in animal models. Spatial resolution and motion artifacts are the main limitations of this technique. Conclusion: Over the last decade, two new techniques for UP vasculari- zation study have emerged to complement the classical 2D Doppler: the 3DPD and new angio-MRI sequences that do not require use of contrast. They provide the ability to quantify perfusion signal directly within the UP unit, and may permit in the near future major progresses both for the understanding of the physiology of the UP visualization and for the pre- diction of PE and IUGR. PL5.2. PLACENTAL STRUCTURE AND FUNCTION IN FETAL GROWTH RESTRICTION AND STILLBIRTH C.P. Sibley a , V. Abrahams b , S. Girard a , L. Higgins a , E.D. Johnstone a , R.L. Jones a , A.E.P. Heazell a a Maternal and Fetal Health Research Centre, University of Manchester, Manchester, UK; b Yale School of Medicine, Yale, USA Stillbirth (defined in the UK as death in utero after 24 weeks gestation) affects ~1/200 pregnancies, a rate which has not changed for 20 years. Recent data suggest 43% of unexplained stillbirths are related to fetal growth restriction (FGR) and therefore to placental dysfunction. Our work tests the hypothesis that there is a particular placental phenotype asso- ciated with stillbirth which could be used alongside other tests to identify at risk women. Investigating the placenta in stillbirth is particularly diffi- cult, because of the varied conditions associated with stillbirth, their fre- quency of occurrence, and changes in the placenta in utero after fetal death. Our current strategy is to study groups of women who are at high risk of adverse pregnancy outcome (APO) including FGR and stillbirth. One such group is women who report reduced fetal movements (RFM) in the third trimester. We have found that women who report RFM within one week of delivery have (1) placentas with characteristics similar to those reported for FGR including altered syncytiotrophoblast turnover and reduced sys- tem A amino acid transporter activity, as compared to women who do not report RFM and have normal pregnancy outcomes (NPO); (2) lower serum concentrations of hCG, hPL and PlGF if they have APO as compared to women with RFM who have NPO; (3) placentas which are smaller, less vascular and which display impaired vascular function following APO as compared to NPO; (4) placentas expressing a pro-inflammatory balance of cytokines and increased numbers of Hofbauer cells, in the absence of detectable infection. These data suggest that there is a distinct placental phenotype in women who experience RFM and have APO; if this could be detected antenatally it would be clinically useful in the identification of those at risk of stillbirth. Non-infectious inflammation might be a causal event in the placental dysfunction. Funded by Tommy’s The Baby Charity. TRA. UNDERLYING MECHANISMS DIRECTING ADAM12-MEDIATED TROPHOBLAST INVASION Mahroo Aghababaei a, b , Sofie Perdu a, b , Alexander G. Beristain a, b a University of British Columbia, Vancouver, BC, Canada; b The Child and Family Research Institute, Vancouver, BC, Canada Terminal differentiation of progenitor villous cytotrophoblasts into inva- sive vascular-remodelling extravillous cytotrophoblasts (EVTs) is a critical process in placental development. Inadequate placentation, resulting in part from altered EVT-directed tissue remodelling, plays a central role in the origins of many pregnancy disorders. EVT invasion is a highly regulated developmental process involving coordinated expression of multiple families of proteases. A Disintegrin and Metalloproteinase 12 (ADAM12) is a multifunctional protein belonging to the ADAM family of metal- loproteinases. ADAM12 exists as two alternatively spliced isoforms: ADAM12L (a transmembrane form) and ADAM12S (a truncated secreted form). ADAM12 is highly expressed in the human placenta and promotes matrix remodelling, cell proliferation and invasion in tumorigenesis. Importantly, low ADAM12 serum levels have been associated with preg- nancies linked to poor pregnancy outcome. In spite of this knowledge, the importance of ADAM12 in directing EVT biology in early placentation is poorly understood. Our study aims to examine the importance of ADAM12 in directing EVT invasion and further aims to identify underlying mecha- nism(s) regulating ADAM12 expression. Utilizing first trimester placental Abstracts / Placenta 35 (2014) A1eA112 A6
Transcript of Placental structure and function in fetal growth restriction and stillbirth
Abstracts / Placenta 35 (2014) A1eA112A6
PL4.3.THE EFFECT OF MATERNAL DIABETES ON FETO-PLACENTALENDOTHELIAL CELLS
Ursula Hiden a, Silvija Cvitic a,b, Francisca Diaz a, Evelyn Jantscher-Krenn a, Gernot Desoye a aDepartment of Obstetrics and Gynecology,Medical Univeristy of Graz, Graz, Austria; b Institute of Cell Biology,Histology and Embryology, Medical University of Graz, Graz, Austria
Gestational diabetes mellitus (GDM) is one of the most frequent preg-nancy pathologies. As other types of diabetes and resulting from theobesity epidemic, GDM is a growing problemworldwide. Even by womenunder good glycaemic control, the maternal diabetic environment causesmetabolic derangements in the fetus. Thus, the fetal environment ischaracterized by hyperglycaemia, hyperinsulinemia, metabolically-induced hypoxia and altered levels of growth factors which affectplacental and fetal development. Histological studies revealed hyper-vascularisation and reduced endothelial expression of cell junction mol-ecules in the placenta. Furthermore, placental vessels show alteredresponse to vaso-relaxing agents. These findings indicate changes inplacental endothelial functions as a consequence of the diabetic envi-ronment in utero.The human placenta is a rich source of primary feto-placental endothelialcells and thus gives a great opportunity to investigate endothelial changesoccurring in pregnancy pathologies such as GDM. These primary feto-placental endothelial cells are well characterized and maintain theirphenotype in vitro.Using these human primary feto-placental endothelial cells, we revealedthat the intrauterine diabetic environment indeed causes sustainablefunctional changes in placental endothelial cells. These changes are rep-resented by altered angiogenesis, proliferation and gene expression. Wespeculate that the endothelial cell phenotype in GDM contributes toaltered placental function and may even reflect changes in the fetuses ofdiabetic mothers.
PL5.1.UTERO-PLACENTAL VASCULARIZATION DURING THE FIRST TRIMESTER:WHAT ARE THE NON-INVASIVE IMAGING TOOLS IN 2014?
Olivier Morel a,b, Anne-Claire Chabot-Lecoanet a,b, Jie Duan a,b, EstellePerdiolle-Galet a,b aRegional Maternity of University, Nancy, France; b IADIInserm U947, Nancy, France
Introduction: The physiopathology of utero-placental (UP) vasculariza-tion development is still partially unknown. Major progresses have beenachieved, such as the description of the myometrial vascular shunt. Majorendpoints, however, such as the perfusion timing of intervillous space bymaternal blood, remain unclear. This review aimed to evaluate availablenon-invasive imaging techniques of UP vascularization during the firsttrimester.
Methods: literature review from Medline.Results: Until recently, 2D Doppler examination was the reference. How-ever, its poor predictive values make it unusable in clinical practice. 3DDoppler angiography (3DPD), more sensitive to slow flow, now allows toquantify flows directly into the UP unit. The predictive value of this test forthe prediction of preeclampsia (PE) and intrauterine growth restriction(IUGR) seems high. However, this technique has two major drawbacks: itsdependence on machine settings and the lack of information as to thedirection of flow, which makes it impossible to disentangle maternal andfetal flow. Performance could be improved by contrast agents. New MRIsequences (BOLD) seem to allow an early diagnosis of IUGR in animalmodels. Spatial resolution and motion artifacts are the main limitations ofthis technique.Conclusion: Over the last decade, two new techniques for UP vasculari-zation study have emerged to complement the classical 2D Doppler: the3DPD and new angio-MRI sequences that do not require use of contrast.They provide the ability to quantify perfusion signal directly within the UPunit, and may permit in the near future major progresses both for the
understanding of the physiology of the UP visualization and for the pre-diction of PE and IUGR.
PL5.2.PLACENTAL STRUCTURE AND FUNCTION IN FETAL GROWTHRESTRICTION AND STILLBIRTH
C.P. Sibley a, V. Abrahams b, S. Girard a, L. Higgins a, E.D. Johnstone a, R.L.Jones a, A.E.P. Heazell a aMaternal and Fetal Health Research Centre,University of Manchester, Manchester, UK; bYale School of Medicine, Yale,USA
Stillbirth (defined in the UK as death in utero after 24 weeks gestation)affects ~1/200 pregnancies, a rate which has not changed for 20 years.Recent data suggest 43% of unexplained stillbirths are related to fetalgrowth restriction (FGR) and therefore to placental dysfunction. Our worktests the hypothesis that there is a particular placental phenotype asso-ciated with stillbirth which could be used alongside other tests to identifyat risk women. Investigating the placenta in stillbirth is particularly diffi-cult, because of the varied conditions associated with stillbirth, their fre-quency of occurrence, and changes in the placenta in utero after fetal death.Our current strategy is to study groups of women who are at high risk ofadverse pregnancy outcome (APO) including FGR and stillbirth. One suchgroup is women who report reduced fetal movements (RFM) in the thirdtrimester. We have found that womenwho report RFMwithin one week ofdelivery have (1) placentas with characteristics similar to those reportedfor FGR including altered syncytiotrophoblast turnover and reduced sys-tem A amino acid transporter activity, as compared to women who do notreport RFM and have normal pregnancy outcomes (NPO); (2) lower serumconcentrations of hCG, hPL and PlGF if they have APO as compared towomen with RFM who have NPO; (3) placentas which are smaller, lessvascular and which display impaired vascular function following APO ascompared to NPO; (4) placentas expressing a pro-inflammatory balance ofcytokines and increased numbers of Hofbauer cells, in the absence ofdetectable infection.
These data suggest that there is a distinct placental phenotype in womenwho experience RFM and have APO; if this could be detected antenatally itwould be clinically useful in the identification of those at risk of stillbirth.Non-infectious inflammation might be a causal event in the placentaldysfunction.Funded by Tommy’s The Baby Charity.
TRA.UNDERLYING MECHANISMS DIRECTING ADAM12-MEDIATEDTROPHOBLAST INVASION
Mahroo Aghababaei a,b, Sofie Perdu a,b, Alexander G.Beristain a,b aUniversity of British Columbia, Vancouver, BC, Canada; b TheChild and Family Research Institute, Vancouver, BC, Canada
Terminal differentiation of progenitor villous cytotrophoblasts into inva-sive vascular-remodelling extravillous cytotrophoblasts (EVTs) is a criticalprocess in placental development. Inadequate placentation, resulting inpart from altered EVT-directed tissue remodelling, plays a central role inthe origins of many pregnancy disorders. EVT invasion is a highly regulateddevelopmental process involving coordinated expression of multiplefamilies of proteases. A Disintegrin and Metalloproteinase 12 (ADAM12) isa multifunctional protein belonging to the ADAM family of metal-loproteinases. ADAM12 exists as two alternatively spliced isoforms:ADAM12L (a transmembrane form) and ADAM12S (a truncated secretedform). ADAM12 is highly expressed in the human placenta and promotesmatrix remodelling, cell proliferation and invasion in tumorigenesis.Importantly, low ADAM12 serum levels have been associated with preg-nancies linked to poor pregnancy outcome. In spite of this knowledge, theimportance of ADAM12 in directing EVT biology in early placentation ispoorly understood. Our study aims to examine the importance of ADAM12in directing EVT invasion and further aims to identify underlying mecha-nism(s) regulating ADAM12 expression. Utilizing first trimester placental
