Article

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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    • "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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    • "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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