Fig. 3.

Molecular signaling in angiogenesis. In tip cells, VEGF/VEGFR2 signaling abrogates PTEN and activates AKT which causes nuclear localization of the YAP transcription factor. Nuclear YAP suppresses pro-proliferative signaling. In addition, VEGF signaling suppresses NOTCH expression while upregulating the NOTCH ligand Delta-like 4 (Dll4). The Dll4 activates NOTCH at the surface of stalk cells after which the NICD activates the expression of VEGFR1 while inhibiting VEGFR2 & 3. The decoy receptor VEGFR1 scavenges VEGF which releases PTEN activity and promotes YAP degradation, but part of the YAP is incorporated in adherens junctions and complexed with VE-Cadherin and α-catenin. These actions render stalk cells proliferative.