A Snail1/Notch1 Signaling Axis Controls Embryonic Vascular Development

Notch1-Delta-like 4 (Dll4) signaling controls vascular development by regulating endothelial cell (EC) targets that modulate vessel wall remodeling and arterial-venous specification. The molecular effectors that modulate Notch signaling during vascular development remain largely undefined. Here we demonstrate that the transcriptional repressor, Snail1, acts as a VEGF-induced regulator of Notch1 signaling and Dll4 expression. EC-specific Snail1 loss-of-function conditional knockout mice die in utero with defects in vessel wall remodeling in association with losses in mural cell investment and disruptions in arterial-venous specification. Snail1 loss-of-function conditional knockout embryos further display up-regulated Notch1 signaling and Dll4 expression that is partially reversed by inhibiting Ɣ-secretase activity in vivo with Dll4 identified as a direct target of Snail1-mediated transcriptional repression. These results document a Snail1-Dll4/Notch1 axis that controls embryonic vascular development.