Integrin alpha9beta1 directly binds to vascular endothelial growth factor (VEGF)-A and contributes to VEGF-A-induced angiogenesis

J Biol Chem. 2007 May 18;282(20):15187-96. doi: 10.1074/jbc.M609323200. Epub 2007 Mar 14.

Abstract

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 alpha9beta1 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 alpha9beta1 and the cognate receptor for VEGF-A, VEGF receptor 2 (VEGF-R2). Unlike alpha3beta1or alphavbeta3 integrins, alpha9beta1 was also found to bind the 121 isoform of VEGF-A. This interaction appears to be biologically significant, because alpha9beta1-blocking antibody dramatically and specifically inhibited angiogenesis induced by VEGF-A165 or -121. Together with our previous findings that alpha9beta1 directly binds to VEGF-C and -D and contributes to lymphangiogenesis, these results identify the integrin alpha9beta1 as a potential pharmacotherapeutic target for inhibition of pathogenic angiogenesis and lymphangiogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Cell Adhesion / drug effects
  • Cell Adhesion / physiology
  • Cell Movement / drug effects
  • Cell Movement / physiology*
  • Cells, Cultured
  • Endothelial Cells / metabolism*
  • Fibroblasts / metabolism
  • Humans
  • Integrins / agonists
  • Integrins / metabolism*
  • Mice
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Physiologic* / drug effects
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor A / pharmacology
  • Vascular Endothelial Growth Factor C / metabolism
  • Vascular Endothelial Growth Factor C / pharmacology
  • Vascular Endothelial Growth Factor D / metabolism
  • Vascular Endothelial Growth Factor D / pharmacology
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Antibodies, Monoclonal
  • Integrins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor D
  • integrin alpha 9 beta 1
  • Vascular Endothelial Growth Factor Receptor-2