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: 6.27). 07/2011; 138(14):2987-98. DOI: 10.1242/dev.066589
Source: PubMed

ABSTRACT 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; DOI:10.1530/REP-13-0474
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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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    • "Genes encoding several components of the Notch signaling pathway are expressed in the placenta of mice and humans, including the ligands (Jagged1, Jagged2, Dll1 and Dll4), receptors (Notch1-4), and downstream transcription factors (Hes1) and their co-repressors of the transducin-like enhancer of split family (Tle2 and Tle3, also known as Groucho or Grg) (Cobellis et al., 2007; De Falco et al., 2007; Gasperowicz and Otto, 2008; Herr et al., 2011; Hunkapiller et al., 2011; Nakayama et al., 1997; Sahin et al., 2011). Notch2 mutants in mice show defects in the placenta and recent conditional mutants have highlighted roles for Notch2 in regulating the development and/or function of spiral artery-associated TGCs (SpA-TGCs) and canal TGCs (C-TGCs), such that mutants in which the Notch2 gene was deleted within spongiotrophoblast cells, which are precursors for SpA-TGCs and C-TGCs, showed diminished maternal blood volume in the spiral arteries, canals and labyrinth (Hamada et al., 1999,2007; Hunkapiller et al., 2011). One of the effects of Notch signaling is transcriptional repression mediated by hairy enhancer of split (HES) transcription factors, which depends on binding TLE co-repressors (Ju et al., 2004). "
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    ABSTRACT: TLE3 is a transcriptional co-repressor that interacts with several DNA-binding repressors, including downstream effectors of the Notch signaling pathway. We generated Tle3-deficient mice and found that they die in utero and their death is associated with abnormal development of the placenta with major defects in the maternal vasculature. In the normal placenta, maternal blood spaces are lined, not as usual in the mammalian circulation by endothelial cells, but rather by specialized embryo-derived cells of the trophoblast cell lineage named trophoblast giant cells (TGC). Tle3 mRNA is expressed in those highly specialized TGC and Tle3 mutants show severe defects in differentiation of TGC-lined channels and lacunar spaces that take blood out of the labyrinth zone of the placenta and into the uterine veins. The mutants also show somewhat milder defects on the arterial-side of the maternal vascular circuit in spiral arteries and canals that take blood into the labyrinth. Notch2 and Tle3 expression patterns overlap in several TGC subtypes and we found that Tle3 and Notch2 mutants have some overlapping features. However, they also show differences implying that TLE3 may mediate some but not all of the effects of Notch2 signaling during placenta development. Therefore, formation of the different types of maternal blood spaces by different TGC subtypes is regulated by distinct molecular mechanisms.
    Developmental Biology 08/2013; 382(1). DOI:10.1016/j.ydbio.2013.08.005 · 3.64 Impact Factor
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