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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    • "Many Notch proteins identified also have roles in vascularization. In the deciduas, Jagged1 immunostaining is reduced in EVTs, which have invaded maternal spiral arteries of pre-eclamptic and HELLP (haemolysis, elevated liver enzymes and low platelet count) pregnancies, regardless of the extent of remodelling (Hunkapiller et al. 2011). It should be noted that this study also shows that Jagged1 is strictly up-regulated as EVTs come into proximity of blood vessels. "
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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.
    Reproduction 12/2013; 147(3). DOI:10.1530/REP-13-0474 · 3.17 Impact Factor
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    • "This is in good accordance with the known role of Notch signaling in vascular patterning and in the specification of arterial identity (Roca and Adams, 2007; Swift and Weinstein, 2009). The core component of this pathway consists of four transmembrane receptors (Notch1–4) and five ligands (Delta1/3/4 and Jagged 1/2) that are dynamically expressed through placental development (Hunkapiller et al., 2011). Conditional deletion of Notch2 in mice leads to significant reduction in placental perfusion and arterial invasion by trophoblasts (Gasperowicz and Otto, 2008). "
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    ABSTRACT: MicroRNAs (miRNAs) have recently become essential actors in various fields of physiology and medicine, especially as easily accessible circulating biomarkers, or as modulators of cell differentiation. To this respect, terminal differentiation of trophoblasts (the characteristic cells of the placenta in Therian mammals) into syncytiotrophoblast, villous trophoblast, or extravillous trophoblast constitutes a good example of such a choice, where miRNAs have recently been shown to play an important role. The aim of this review is to provide a snapshot of what is known today in placentation mechanisms that are mediated by miRNA, under the angles of materno-fetal immune dialog regulation, trophoblast differentiation, and angiogenesis at the materno-fetal interface. Also, two aspects of regulation of these issues will be highlighted: the part played by oxygen concentration and the specific function of imprinted genes in the developing placenta.
    Frontiers in Genetics 11/2013; 4:248. DOI:10.3389/fgene.2013.00248
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    • "Interestingly, various mRNAs such as BAMBI, a marker of metastasis in colon cancer (Fritzmann et al., 2009), insulin-like growth factor 2 (IGF2), inducible nitric oxide synthase (iNOS), fibronectin 1 (FN1), MMP-2, Notch2, uPAR, and Snai1 (also known as Snail1), which are all direct targets of TCF/β -catenin1, were found to be increased in the EVT pools concomitant with the upregulation of TCF-4 (Figure 3). Indeed, these genes have already been implicated in the control of trophoblast motility (Bischof et al., 2000; Lala and Chakraborty, 2003; Harris et al., 2008; Hunkapiller et al., 2011). Therefore, we speculate that nuclear recruitment of β -catenin and increased expression of TCF-4 in EVTs drives a set of genes promoting trophoblast invasion and migration. "
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    ABSTRACT: Wingless ligands, a family of secreted proteins, are critically involved in organ development and tissue homeostasis by ensuring balanced rates of stem cell proliferation, cell death and differentiation. Wnt signaling components also play crucial roles in murine placental development controlling trophoblast lineage determination, chorioallantoic fusion and placental branching morphogenesis. However, the role of the pathway in human placentation, trophoblast development and differentiation is only partly understood. Here, we summarize our present knowledge about Wnt signaling in the human placenta and discuss its potential role in physiological and aberrant trophoblast invasion, gestational diseases and choriocarcinoma formation. Differentiation of proliferative first trimester cytotrophoblasts into invasive extravillous trophoblasts is associated with nuclear recruitment of β -catenin and induction of Wnt-dependent T-cell factor 4 suggesting that canonical Wnt signaling could be important for the formation and function of extravillous trophoblasts. Indeed, activation of the pathway was shown to promote trophoblast invasion in different in vitro trophoblast model systems as well as trophoblast cell fusion. Methylation-mediated silencing of inhibitors of Wnt signaling provided evidence for epigenetic activation of the pathway in placental tissues and choriocarcinoma cells. Similarly, abundant nuclear expression of β -catenin in invasive trophoblasts of complete hydatidiform moles suggested a role for hyper-activated Wnt signaling. In contrast, upregulation of Wnt inhibitors was noticed in placentae of women with preeclampsia, a disease characterized by shallow trophoblast invasion and incomplete spiral artery remodeling. Moreover, changes in Wnt signaling have been observed upon cytomegalovirus infection and in recurrent abortions. In summary, the current literature suggests a critical role of Wnt signaling in physiological and abnormal trophoblast function.
    Frontiers in Genetics 09/2013; 4:190. DOI:10.3389/fgene.2013.00190
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