Integrin α9β1 directly binds to vascular endothelial growth factor (VEGF)- a and contributes to VEGF-A-induced angiogenesis

Vascular endothelial growth factor A (VEGF-A) is a potent inducer of angiogenesis. We now show that VEGF-A-induced adhesion and migration of human endothelial cells are dependent on the integrin alpha 9 beta 1 and that VEGF-A is a direct ligand for this integrin. Adhesion and migration of these cells on the 165 and 121 isoforms of VEGF-A depend on cooperative input from alpha 9 beta 1 and the cognate receptor for VEGF-A, VEGF receptor 2 (VEGF-R2). Unlike alpha 3 beta 1 or alpha v beta 3 integrins, alpha 9 beta 1 was also found to bind the 121 isoform of VEGF-A. This interaction appears to be biologically significant, because alpha 9 beta 1-blocking antibody dramatically and specifically inhibited angiogenesis induced by VEGF-A165 or -121. Together with our previous findings that alpha 9 beta 1 directly binds to VEGF-C and -D and contributes to lymphangiogenesis, these results identify the integrin alpha 9 beta 1 as a potential pharmacotherapeutic target for inhibition of pathogenic angiogenesis and lymphangiogenesis.