Role of alpha(v)beta(3) integrin in the activation of vascular endothelialgrowth factor receptor-2

Interaction between integrin alpha(v)beta(3) and extracellular matrix is cr ucial for endothelial cells sprouting from capillaries and for angiogenesis , Furthermore, integrin-mediated outside-in signals co-operate with growth factor receptors to promote cell proliferation and motility, To determine a potential regulation of angiogenic inducer receptors by the integrin syste m, we investigated the interaction between alpha(v)beta(3) integrin and tyr osine kinase vascular endothelial growth factor receptor-2 (VEGFR-2) in hum an endothelial cells, We report that tyrosine-phosphorylated VEGFR-2 co-imm unoprecipitated with beta 3 integrin subunit, but not with beta 1 or beta 5 , from cells stimulated with VEGF-A(165) VEGFR-2 phosphorylation and mitoge nicity induced by VEGF-A(165) were enhanced in cells plated on the alpha(v) beta(3) ligand, vitronectin, compared with cells plated on the alpha(5)beta (1) ligand, fibronectin or the alpha(2)beta(1) ligand, collagen. BV4 anti-b eta 3 integrin mAb, which does not interfere with endothelial fell adhesion to vitronectin, reduced (i) the tyrosine phosphorylation of VEGFR-2; (ii) the activation of downstream transductor phasphoinositide 3-OH kinase; and (iii) biological effects triggered by VEGF-A165 These results indicate a ne w role for alpha(v)beta(3) integrin in the activation of an in vitro angiog enic program in endothelial cells. Besides being the most important surviva l system for nascent vessels by regulating cell adhesion to matrix, alpha(v )beta(3) integrin participates in the full activation of VEGFR-2 triggered by VEGF-A, which is an important angiogenic inducer in tumors, inflammation and tissue regeneration.