VE-cadherin Stimulates Syndecan-1-Coupled IGF1R and Cross-Talk between alphaVbeta3 Integrin and VEGFR2 During the Onset of Endothelial Cell Dissemination in Angiogenesis

VEGF-stimulated angiogenesis depends on a cross-talk mechanism involving VEGF receptor 2 (VEGFR2), vascular endothelial (VE)-cadherin and the αVβ3 integrin. Since we have shown that αVβ3 integrin activation is dependent on its incorporation, along with the insulin-like growth factor-1 receptor (IGF1R) kinase, into a ternary receptor complex organized by the matrix receptor syndecan-1 (Sdc1), we questioned the role of this core complex in VEGF-stimulated angiogenesis. We find that the Sdc1-coupled ternary receptor complex is required for VEGF signaling and for stimulation of vascular endothelial cell migration by VE-cadherin engagement. VE-cadherin binding to Fc/VE-cadherin chimeras activates Sdc1-coupled IGF1R and αVβ3 integrin; this depends on VEGFR2 and c-Src activated by the cadherin. Blocking homotypic VE-cadherin engagement disrupts VEGF-stimulated cell migration, which is restored by clustering the cadherin in the absence of cell-cell adhesion. This cadherin-dependent stimulation requires VEGFR2 and IGF1R and is blocked by synstatin (SSTN 92-119 ), a peptide that competitively disrupts the Sdc1-coupled ternary complex and prevents αVβ3 integrin activation that is required for VEGFR2 activation. VEGFR2-stimulated angiogenesis in the mouse aortic ring explant assay is disrupted by SSTN, but only early in the process, suggesting that IGF1R coupling to Sdc1 and αVβ3 integrin comprises a core activation mechanism activated by VE-cadherin that is necessary for VEGFR2 and integrin activation during the initial stages of endothelial cell dissemination during angiogenesis.