Tip/stalk cell specification during spouting angiogenesis and vascular development. Angiogenic sprouts emerge from the newly formed vessels in response to pro-angiogenic cues, such as hypoxia-induced VEGF. VEGF stimulus, acting via VEGFR-2, increases the expression of Dll4 on endothelial cells, which in turn activates Notch receptors on adjacent endothelial cells. Furthermore, VEGFRs are regulated by Notch signaling, providing an additional feedback loop between the two pathways: activated Notch receptors on ECs can positively regulate the expression of VEGFR-1 and VEGFR-3 in those cells. In contrast, Notch activation leads to the reduction of VEGFR-2 expression in cell culture and a concomitant decrease in the proangiogenic response to exogenous VEGF. Both of these effects would likely lead to a lower migratory or proliferative response in connector cells that exhibit Notch activation.