3.4.2. Epidermal Growth Factor-Like Domain 7

Recently, we demonstrated that migration and invasion of trophoblast cells is regulated by the secreted factor Epidermal growth factor-like domain 7 (EGFL7), a novel NOTCH interactor. EGFL7 activates NOTCH1, MAPK and AKT signaling pathways in both trophoblast cell lines and primary cells [273]. Activation of the NOTCH pathway is important in both interstitial and endovascular invasion by trophoblast cells. In vitro functional assays show that invasion of Matrigel by trophoblast cells overexpressing EGFL7 is impaired in the presence of a γ-secretase inhibitor, normally used to inhibit NOTCH activation [264,273]. NOTCH appears to be also involved in trophoblast endovascular invasion, since uNK, involved in the disruption of endometrial spiral arteries integrity, express NOTCH1 and 2 and maternal cells surrounding spiral arteries express DLL1 [264], and NOTCH activation may lead to arterial wall disruption. These results are further confirmed by the fact that NOTCH pathway is dysregulated in placenta of women affected by preeclampsia [264,274–280], a common pregnancy disorder characterized by an insufficient trophoblast invasion and an inadequate vascular remodeling. In women affected by preeclampsia, the alteration of NOTCH pathway is accompanied by a concomitant altered expression of EGFL7, in both placenta and maternal circulation [274,281].
