Regulation of angiogenesis in vivo by ligation of integrin alpha 5 beta 1 with the central cell-binding domain of fibronectin

Angiogenesis depends on the cooperation of growth factors and cell adhesion events, Although alpha v integrins have been shown to play critical roles in angiogenesis, recent studies in alpha-null mice suggest that other adhes ion receptors and their ligands also regulate this process. Evidence is now provided that the integrin alpha 5 beta 1 and its ligand fibronectin are c oordinately up-regulated on blood vessels in human tumor biopsies and play critical roles in angiogenesis, resulting in tumor growth in vivo. Angiogen esis induced by multiple growth factors in chick embryos was blocked by mon oclonal antibodies to the cell-binding domain of fibronectin. Furthermore, application of fibronectin or a proteolytic fragment of fibronectin contain ing the central cell-binding domain to the chick chorioallantoic membrane e nhanced angiogenesis in an integrin alpha 5 beta 1-dependent manner, Import antly, antibody, peptide, and novel nonpeptide antagonists of integrin alph a 5 beta 1 blocked angiogenesis induced by several growth factors but had l ittle effect on angiogenesis induced by vascular endothelial growth factor (VEGF) in both chick embryo and murine models, In fact, these alpha 5 beta 1 antagonists inhibited tumor angiogenesis, thereby causing regression of h uman tumors in animal models. Thus, fibronectin and integrin alpha 5 beta 1 , like integrin alpha v beta 3, contribute to an angiogenesis pathway that is distinct from VEGF-mediated angiogenesis, yet important for the growth o f tumors.