Angiogenesis promoted by vascular endothelial growth factor: Regulation through α(1)β(1 )and α(2)β(1 )integrins

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is a cytokine of central importance for the angiogenesis associated with cancers and other pathologies. Because angiogenesis often involves endothelial cell (EC) migration and proliferation within a collagen-rich extracellular matrix, we investigated the possibility that VEGF promotes neovascularization through regulation of collagen receptor expression. VEGF induced a 5- to 7-fold increase in dermal microvascular EC surface protein expression of two collagen receptors—the α(1)β(1) and α(2)β(1) integrins—through induction of mRNAs encoding the α(1) and α(2) subunits. In contrast, VEGF did not induce increased expression of the α(3)β(1) integrin, which also has been implicated in collagen binding. Integrin α(1)-blocking and α(2)-blocking antibodies (Ab) each partially inhibited attachment of microvascular EC to collagen I, and α(1)-blocking Ab also inhibited attachment to collagen IV and laminin-1. Induction of α(1)β(1) and α(2)β(1) expression by VEGF promoted cell spreading on collagen I gels which was abolished by a combination of α(1)-blocking and α(2)-blocking Abs. In vivo, a combination of α(1)-blocking and α(2)-blocking Abs markedly inhibited VEGF-driven angiogenesis; average cross-sectional area of individual new blood vessels was reduced 90% and average total new vascular area was reduced 82% without detectable effects on the pre-existing vasculature. These data indicate that induction of α(1)β(1) and α(2)β(1) expression by EC is an important mechanism by which VEGF promotes angiogenesis and that α(1)β(1) and α(2)β(1) antagonists may prove effective in inhibiting VEGF-driven angiogenesis in cancers and other important pathologies.