Figure 1.

Canonical Notch signaling and crosstalk with VEGF signaling. VEGF signaling up-regulates the expression of Notch ligands and receptors on ECs. Notch ligands on the signal-sending cell trigger Notch receptors on the adjacent signal-receiving cell, leading to receptor cleavage by ADAM and γ-secretase and the release of NICD. NICD translocates into the nucleus, where it associates with RBP-J, and converts RBP-J from a transcriptional repressor into an activator by recruiting transcriptional coactivators (CoA) to replace coreppressors (CoR). The transcription of target genes such as Hes are turned on. The p21 expression is also regulated by Notch activation. Notch signaling downregulates VEGFR2 and upregulates VEGFR1, leading to differentiation of tip and stalk cells, among other changes of ECs during angiogenesis.