Abstract

Interaction between integrin _v3 and extracellular matrix is crucial 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 system, we investigated the interaction between _v3 integrin and tyrosine kinase vascular endothelial growth factor receptor-2 (VEGFR-2) in human endothelial cells. We report that tyrosine-phosphorylated VEGFR-2 co-immunoprecipitated with 3 integrin subunit, but not with 1 or 5, from cells stimulated with VEGF-A₁₆₅. VEGFR-2 phosphorylation and mitogenicity induced by VEGF-A₁₆₅ were enhanced in cells plated on the _v3 ligand, vitronectin, compared with cells plated on the ₅₁ ligand, fibronectin or the ₂₁ ligand, collagen. BV4 anti-3 integrin mAb, which does not interfere with endothelial cell adhesion to vitronectin, reduced (i) the tyrosine phosphorylation of VEGFR-2; (ii) the activation of downstream transductor phosphoinositide 3-OH kinase; and (iii) biological effects triggered by VEGF-A₁₆₅. These results indicate a new role for _v3 integrin in the activation of an in vitro angiogenic program in endothelial cells. Besides being the most important survival system for nascent vessels by regulating cell adhesion to matrix, _v3 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.