Figure 8.

Spatial and temporal modulation of VEGFR2 signaling occurs in discrete subcellular compartments. (a) In the basal state, caveolin-1 (Cav1) negatively modulates VEGFR2 by binding to the receptor in caveolae/lipid rafts. VEGF initiates activation of VEGFR2 by promoting dissociation of Cav1 from the receptor. Once released, activated VEGFR2 localizes with phosphorylated Cav1 and paxillin (Pax) at focal adhesions/complexes to initiate downstream signaling. Growth factor stimulation also recruits small GTPases, ARF6 and Rac1, to activate Nox complexes located in caveolae/lipid rafts. Localized production of H₂O₂ acts as a secondary messenger during VEGF signaling to promote angiogenesis, proliferation, and migration in endothelial cells (ECs). (b) Endothelial migration is a key event that occurs during angiogenesis in ECs. Cell-cell adhesions are mediated by interactions between VE-cadherin and IQGAP1, which are disrupted upon VEGF stimulation to initiate the migration process. During active migration, IQGAP1 functions as a scaffolding protein to recruit signaling components such as activated VEGFR2, Nox, and Rac1 to the leading edge. Additionally, Nox-derived H₂O₂ induces localized sulfenic acid formation in IQGAP1 to promote directional migration events. Adapted from Ushio-Fukai, 2007.