ANGIOGENESIS PROMOTED BY VASCULAR ENDOTHELIAL GROWTH-FACTOR - REGULATION THROUGH ALPHA(1)BETA(1) AND ALPHA(2)BETA(1) INTEGRINS

Vascular endothelial growth factor (VEGF), also known as vascular perm eability factor, is a cytokine of central importance for the angiogene sis associated with cancers and other pathologies, Because angiogenesi s often involves endothelial cell (EC) migration and proliferation wit hin a collagen-rich extracellular matrix, we investigated the possibil ity that VEGF promotes neovascularization through regulation of collag en receptor expression, VEGF induced a 5- to 7-fold increase in dermal microvascular EC surface protein expression of two collagen receptors -the alpha(1) beta(1) and alpha(2) beta(1) integrins-through induction of mRNAs encoding the alpha(1) and alpha(2) subunits, In contrast, VE GF did not induce increased expression of the alpha(3) beta(1) integri n, which also has been implicated in collagen binding, Integrin alpha( 1)-blocking and alpha(2)-blocking antibodies (Ab) each partially inhib ited attachment of microvascular BC to collagen I, and anti-blocking A b also inhibited attachment to collagen IV and laminin-l. Induction of alpha(1) beta(1) and alpha(2) beta(1) expression by VEGF promoted cel l spreading on collagen I gels which mas abolished by a combination of alpha(1)-blocking and a blocking Abs. In vitro, a combination of alph a(1)-blocking and alpha(2)-blocking hhs markedly inhibited VEGF-driven angiogenesis; average cross-sectional area of individual new blood ve ssels 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 alpha(1) beta(1) and alpha(2) beta(1) expression by the EC is an important mechanism by which VEGF promotes angiogenesis and that alpha(1) beta(1) and alpha(2) beta(1) antagonist s may prove effective in inhibiting VEGF-driven angiogenesis in cancer s and other important pathologies.