Angiogenesis promoted by vascular endothelial growth factor: Regulation through α1β1and α2β1 integrins

Abstract

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.