Villous trophoblast abnormalities in extremely preterm deliveries with elevated second trimester maternal serum hCG or inhibin-A

Fitzgerald, Brendan; Levytska, Khrystyna; Kingdom, John; Walker, Mark; Baczyk, Dora; Keating, Sarah

doi:10.1016/j.placenta.2011.01.018

Cited by 58 publications

(46 citation statements)

References 19 publications

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“…77 The GCM1 axis, which controls differentiation of both types of trophoblasts, is disrupted in severely preeclamptic placental villi to favor a reduction in syncytial fusion [78][79][80][81] and is accentuated by hypoxia-mediated degradation of GCM1. 82 Patchy areas of apoptosis, excess syncytial knot formation, and areas of necrosis are found in severe preeclamptic placental villi 83 and can be reproduced in vitro, respectively, by hypoxic culture 84 or hypoxia-reoxygenation 77 in cultured first-trimester placental villous explants. Large syncytial knots secrete sFlt1 into maternal blood in severely preeclamptic women.…”

Section: Placental Pathology Of Severe Pementioning

confidence: 99%

Is heparin a placental anticoagulant in high-risk pregnancies?

Kingdom

Drewlo

2011

Blood

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Randomized control trials show beneficial effects of heparin in high-risk pregnancies to prevent preeclampsia and intrauterine growth restriction. However, the lack of placental pathology data in these trials challenges the assumption that heparin is a placental anticoagulant. Recent data show that placental infarction is probably associated with abnormalities in development of the placenta, characterized by poor maternal perfusion and an abnormal villous trophoblast compartment in contact with maternal blood, than with maternal thrombophilia. At-risk pregnancies may therefore be predicted by noninvasive prenatal testing of placental function in mid-pregnancy. Heparin has diverse cellular functions that include direct actions on the trophoblast. Dissecting the non-anticoagulant actions of heparin may indicate novel and safer therapeutic targets to prevent the major placental complications of pregnancy. IntroductionA small subset of reproductive-aged women require anticoagulation in the context of a mechanical heart valve 1 or to prevent recurrent venous thromboembolism as in women with antiphospholipid syndrome. 2 When planning pregnancy, they mostly convert from an oral anticoagulant such as Coumadin to subcutaneous injections of heparin to avoid the potential embryopathy induced by transplacental passage of Coumadin. 3 By doing so, they expose themselves to relatively minor side effects such as skin bruising and, because heparin promotes bone loss, to the rare possibility of vertebral bone compression fractures and neurologic complications. 4 In this context heparin is a success story for women whose predecessors were counseled to avoid attempts at motherhood. More than 35 years ago the concept of placental anticoagulation was proposed for women in subsequent pregnancies after recurrent placental infarction. 5 Since then we have witnessed an exponential increase in the prescription of heparin to pregnant women for a wide variety of indications, based on a common theme that superior placental function can be attained via its anticoagulant properties. The fashion has spread widely according to claims that heparin promotes successful implantation after in vitro fertilization, 6,7 prevents recurrent miscarriages, 8 promotes better outcomes in the perinatal period, 9 and, finally, may be used vaginally to induce labor in full-term pregnancies. 10 A common aspect of these studies is the use of safer low molecular weight heparins (LMWHs) in prophylactic regimes that have a low risk of serious side effects when used over a relatively short duration of time in pregnancy. However, the current cost per pregnancy to prescribe prophylactic LMWH is ϳ $3000, a significant burden to uninsured women in countries, such as Canada, with variable employer-based drug plans. Ongoing use of such drugs for these indications in pregnancy therefore deserves more rigorous evidence. Recent impressive but negative trials are making progress by limiting the scope of use in women with recurrent miscarriage. Heparins are complex macromol...

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Section: Placental Pathology Of Severe Pementioning

confidence: 99%

Is heparin a placental anticoagulant in high-risk pregnancies?

Kingdom

Drewlo

2011

Blood

View full text Add to dashboard Cite

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“…Molecular interactions at the embryo-maternal interface during the time of adhesion and subsequent invasion are crucial for implantation [1]. Failure of these interactions can lead to preeclampsia (PE), early pregnancy loss or intrauterine growth retardation (IUGR).…”

Section: Introductionmentioning

confidence: 99%

“…Failure of these interactions can lead to preeclampsia (PE), early pregnancy loss or intrauterine growth retardation (IUGR). There is evidence suggesting that cytokines that are produced by the developing placenta play an important role in these processes [1]. We have recently determined the role of a new actor in these processes [2,3], endocrine glandderived vascular endothelial growth factor (EG-VEGF), also known as prokineticin 1 (PROK1).…”

Section: Introductionmentioning

confidence: 99%

Revisiting the role of hCG: new regulation of the angiogenic factor EG-VEGF and its receptors

Brouillet

Hoffmann

Chauvet

et al. 2011

Cell. Mol. Life Sci.

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Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor reported to be specific for endocrine tissues, including the placenta. Its biological activity is mediated via two G protein-coupled receptors, prokineticin receptor 1 (PROKR1) and prokineticin receptor 2 (PROKR2). We have recently shown that (i) EG-VEGF expression peaks between the 8th and 11th weeks of gestation, (ii) its mRNA and protein levels are up-regulated by hypoxia, (iii) EG-VEGF is a negative regulator of trophoblast invasion and (iv) its circulating levels are increased in preeclampsia (PE), the most threatening pathology of pregnancy. Here, we investigated the regulation of the expression of EG-VEGF and its receptors by hCG, a key pregnancy hormone that is also deregulated in PE. During the first trimester of pregnancy, hCG and EG-VEGF exhibit the same pattern of expression, suggesting that EG-VEGF is potentially regulated by hCG. Both placental explants (PEX) and primary cultures of trophoblasts from the first trimester of pregnancy were used to investigate this hypothesis. Our results show that (i) LHCGR, the hCG receptor, is expressed both in cyto- and syncytiotrophoblasts, (ii) hCG increases EG-VEGF, PROKR1 and PROKR2 mRNA and protein expression in a dose- and time-dependent manner, (iii) hCG increases the release of EG-VEGF from PEX conditioned media, (iv) hCG effects are transcriptional and post-transcriptional and (v) the hCG effects are mediated by cAMP via cAMP response elements present in the EG-VEGF promoter region. Altogether, these results demonstrate a new role for hCG in the regulation of EG-VEGF and its receptors, an emerging regulatory system in placental development.

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“…Syncytiotrophoblast plays a vital role in regulating nutrient, water, waste, and gas exchange between maternal and fetal circulations and produces various hormones vital for fetal development and the maintenance of human pregnancy (2). Because of its importance for fetal health and development, disruptions in syncytiotrophoblast formation or functionality can have devastating consequences for pregnancy (3)(4)(5).…”

mentioning

confidence: 99%

OVO-like 1 regulates progenitor cell fate in human trophoblast development

Renaud

Chakraborty

Mason

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Epithelial barrier integrity is dependent on progenitor cells that either divide to replenish themselves or differentiate into a specialized epithelium. This paradigm exists in human placenta, where cytotrophoblast cells either propagate or undergo a unique differentiation program: fusion into an overlying syncytiotrophoblast. Syncytiotrophoblast is the primary barrier regulating the exchange of nutrients and gases between maternal and fetal blood and is the principal site for synthesizing hormones vital for human pregnancy. How trophoblast cells regulate their differentiation into a syncytium is not well understood. In this study, we show that the transcription factor OVO-like 1 (OVOL1), a homolog of Drosophila ovo, regulates the transition from progenitor to differentiated trophoblast cells. OVOL1 is expressed in human placenta and was robustly induced following stimulation of trophoblast differentiation. Disruption of OVOL1 abrogated cytotrophoblast fusion and inhibited the expression of a broad set of genes required for trophoblast cell fusion and hormonogenesis. OVOL1 was required to suppress genes that maintain cytotrophoblast cells in a progenitor state, including MYC, ID1, TP63, and ASCL2, and bound specifically to regions upstream of each of these genes. Our results reveal an important function of OVOL1 as a regulator of trophoblast progenitor cell fate during human trophoblast development.epithelial barrier | placenta | trophoblast | OVO-like 1 | differentiation E pithelial cells turn over regularly and are reliant on a pool of cells that either replenish the reservoir of progenitor cells or differentiate into the specialized epithelium required for that tissue's function. An excellent paradigm of epithelial turnover exists in the human placenta, where mononuclear cytotrophoblast cells lining the inner portion of the chorionic villi comprise the progenitor cells of the placental epithelium. These cells either propagate to maintain an adequate reservoir of progenitor cells or undergo a differentiation program that results in fusion with an overlying syncytium (1). This syncytium, termed "syncytiotrophoblast," forms the principal epithelial barrier separating maternal and fetal blood. Syncytiotrophoblast plays a vital role in regulating nutrient, water, waste, and gas exchange between maternal and fetal circulations and produces various hormones vital for fetal development and the maintenance of human pregnancy (2). Because of its importance for fetal health and development, disruptions in syncytiotrophoblast formation or functionality can have devastating consequences for pregnancy (3-5).Syncytiotrophoblast has a limited lifespan and is shed into the maternal circulation throughout pregnancy (6, 7). Therefore, to maintain the integrity of the maternal-fetal exchange surface, syncytiotrophoblast is continually replenished by select populations of cytotrophoblast cells that forego self-renewal and instead fuse into the overlying syncytiotrophoblast. This feature, analogous to paradigms established in othe...

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Villous trophoblast abnormalities in extremely preterm deliveries with elevated second trimester maternal serum hCG or inhibin-A

Cited by 58 publications

References 19 publications

Is heparin a placental anticoagulant in high-risk pregnancies?

Is heparin a placental anticoagulant in high-risk pregnancies?

Revisiting the role of hCG: new regulation of the angiogenic factor EG-VEGF and its receptors

OVO-like 1 regulates progenitor cell fate in human trophoblast development

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