A role for Notch signaling in trophoblast endovascular invasion and in the pathogenesis of pre-eclampsia

Center for Reproductive Sciences, University of California-San Francisco, CA 94143, USA.
Development (Impact Factor: 6.46). 07/2011; 138(14):2987-98. DOI: 10.1242/dev.066589
Source: PubMed


Placental trophoblasts (TBs) invade and remodel uterine vessels with an arterial bias. This process, which involves vascular mimicry, re-routes maternal blood to the placenta, but fails in pre-eclampsia. We investigated Notch family members in both contexts, as they play important roles in arterial differentiation/function. Immunoanalyses of tissue sections showed step-wise modulation of Notch receptors/ligands during human TB invasion. Inhibition of Notch signaling reduced invasion of cultured human TBs and expression of the arterial marker EFNB2. In mouse placentas, Notch activity was highest in endovascular TBs. Conditional deletion of Notch2, the only receptor upregulated during mouse TB invasion, reduced arterial invasion, the size of maternal blood canals by 30-40% and placental perfusion by 23%. By E11.5, there was litter-wide lethality in proportion to the number of mutant offspring. In pre-eclampsia, expression of the Notch ligand JAG1 was absent in perivascular and endovascular TBs. We conclude that Notch signaling is crucial for TB vascular invasion.

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    • "Proper trophoblast invasion of maternal spiral arteries in the uterine decidua is integral to placenta formation. Notch proteins are implicated in EC-trophoblast interactions during this vascular remodeling in the uterine decidua[76]. Our data set the stage for genetic studies to evaluate the requirement for Notch signaling in decidual angiogenesis and early placentation. "
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    ABSTRACT: Angiogenesis is essential for uterine decidualization, the progesterone-mediated transformation of the uterus allowing embryo implantation and initiation of pregnancy. In the current study, we define the vasculature, expression of Notch proteins and Notch ligands, and Notch activity in both endothelial cells and vascular-associated mural cells of blood vessels in the pre-implantation endometrium and post-implantation decidua of the mouse uterus. We used immunofluorescence to determine the expression of Notch in endothelial cells and mural cells by co-staining for the endothelial cell marker, CD31, the pan-mural cell marker, platelet-derived growth factor receptor beta (PDGFR-β), the pericyte markers, neural/glial antigen 2 (NG2) and desmin, or the smooth muscle cell marker, alpha smooth muscle actin (SMA). A fluorescein isothiocyanate-labeled dextran tracer, was used to identify functional peri-implantation vasculature. CBF:H2B-Venus Notch reporter transgenic mice were used to determine Notch activity. Notch signaling is observed in endothelial cells and pericytes in the peri-implantation uterus. Prior to implantation, Notch1, Notch2 and Notch4 and Notch ligand, Delta-like 4 (Dll4) are expressed in capillary endothelial cells, while Notch3 is expressed in the pericytes. Jagged1 is expressed in both capillary endothelial cells and pericytes. After implantation, Notch1, Notch4 and Dll4 are expressed in endothelial cells of newly formed decidual capillaries. Jagged1 is expressed in endothelial cells of spiral arteries and a subset of decidual pericytes. Notch proteins are not expressed in lymphatic vessels or macrophages in the peri-implantation uterus. We show Notch activity and distinct expression patterns for Notch proteins and ligands, suggesting unique roles for Notch1, Notch4, Dll4, and Jag1 during decidual angiogenesis and early placentation. These data set the stage for loss-of-function and gain-of-function studies that will determine the cell-type specific requirements for Notch proteins in decidual angiogenesis and placentation.
    Full-text · Article · Dec 2015 · Vascular Cell
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    • "Moreover, in RBPJk mutant mice chorioallantoic fusion is blocked and the number of spongiotrophoblasts is reduced, suggesting that the canonical Notch pathway could be important for proliferation and/or suppression of apoptosis of this cell type (Oka et al., 1995;Krebs et al., 2004). Moreover, Notch2 has been implicated in motility of murine glycogen and trophoblast giant cells since a conditional knock-out of the gene in their progenitors affected endovascular invasion and placental perfusion (Hunkapiller et al., 2011).Recent studies conducted in our laboratory also suggested that Notch signalling could be critically involved in controlling CCT proliferation and invasive differentiation. Immunofluorescence of first trimester placental tissues revealed expression of Notch1, 2 and 3 in trophoblast cell columns, whereas EVTs only expressed Notch2, suggesting that activity of the Notch pathway could be largely confined to proliferative trophoblast progenitors (Haider et al., 2014). "
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    ABSTRACT: Abnormal development of invasive trophoblasts has been implicated in the pathogenesis of human pregnancy diseases such as preeclampsia. However, critical signalling pathways controlling formation and differentiation of these cells have been poorly elucidated. Here, we provide evidence that the canonical Notch pathway, operating through Notch-dependent activation of its key regulatory transcription factor RBPJκ, controls proliferation and differentiation in villous explant cultures and primary trophoblasts of early pregnancy. Immunofluorescence of first trimester placental tissue revealed expression of RBPJκ and its co-activators, the MAML proteins, in nuclei of proliferative cell column trophoblasts and differentiated, extravillous trophoblasts. However, RBPJκ expression, transcript levels of the Notch target gene HES1 and activity of a Notch/RBPJκ-dependent luciferase reporter decreased during in vitro differentiation of primary cytotrophoblasts on fibronectin. Silencing of RBPJκ using siRNAs increased proliferation of cell column trophoblasts in floating villous explant cultures analysed by outgrowth and BrdU labelling. Similarly, downregulation of the transcription factor enhanced BrdU incorporation in isolated primary cultures. However, motility of these cells was not affected. In addition, gene silencing of RBPJκ increased cyclin D1 expression in the two trophoblast model systems as well as markers of the differentiated, extravillous trophoblast, i.e. integrin α1, ADAM12 and T-cell factor 4. In summary, the data suggest that Notch-dependent RBPJκ activity could be required for balanced rates of trophoblast proliferation and differentiation in human placental anchoring villi preventing exaggerated trophoblast overgrowth as well as premature formation of extravillous trophoblasts.
    Preview · Article · May 2014 · Molecular Human Reproduction
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    • "Notch2 localizes to maternal sinusoidal trophoblasts in the mouse placental labyrinth, the site of fetal–maternal exchange, and from the histology of early Notch2- deficient placentas, poor maternal blood sinus formation was evident (Hamada et al. 2007). More recently, conditional deletion under the Tpbpa promoter (Simmons et al. 2007) specific for invasive spiral arteriole giant trophoblast Cell (TGC) and glycogen trophoblast cell lineages has shown impaired trophoblast invasion into the maternal arteries and reduced maternal canal size and placental perfusion (Hunkapiller et al. 2011). Taken together, these findings imply a fundamental role for Notch2 signalling in endovascular trophoblast invasion in the mouse placenta. "
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    ABSTRACT: The establishment of a successful pregnancy requires the implantation of a competent blastocyst into a 'receptive' endometrium, facilitating the formation of a functional placenta. Inadequate or inappropriate implantation and placentation is a major reason for infertility and is thought to lead to first trimester miscarriage, placental insufficiency and other obstetric complications. Blastocyst-endometrial interactions are critical for implantation and placental formation.The Notch signalling family is a receptor-ligand family that regulates cellular processes as diverse as proliferation, apoptosis, differentiation, invasion and adhesion. Notch signalling is achieved via cell-cell interaction, thus, via Notch, cells can have direct effects on the fate of their neighbours. Recently, a number of studies have identified Notch receptors and ligands in the endometrium, blastocyst and placenta. This review collates current knowledge of this large receptor-ligand family and explores the role of Notch signalling during implantation and placentation, drawing on information from both human and animal studies. Overall, the evidence suggests that Notch signalling is a critical component of fetal-maternal communication during implantation and placentation and that abnormal Notch expression is associated with impaired placentation and preeclampsia.
    Full-text · Article · Dec 2013 · Reproduction
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