ALPHA(V)BETA(3)-INTEGRIN MEDIATES THE CELL-ADHESIVE CAPACITY AND BIOLOGICAL-ACTIVITY OF BASIC FIBROBLAST GROWTH-FACTOR (FGF-2) IN CULTURED ENDOTHELIAL-CELLS

Fibroblast growth factor-2 (FGF-2) immobilized on non-tissue culture p lastic promotes adhesion and spreading of bovine and human endothelial cells that are inhibited by anti-FGF2 antibody. Heat-inactivated FGF- 2 retains its cell-adhesive activity despite its incapacity to bind to tyrosine-kinase FGF receptors or to cell-surface heparan sulfate prot eoglycans. Recombinant glutathione-S-transferase-FGF-2 chimeras and sy nthetic FGF-2 fragments identify two cell-adhesive domains in FGF-2 co rresponding: to amino acid sequences 38-61 and 82-101. Both regions ar e distinct from the FGF-receptor-binding domain of FGF-2 and contain a DGR sequence that is the inverse of the RGD cell-recognition sequence . Calcium deprivation, RGD-containing eptapeptides, soluble vitronecti n (VN), but not fibronectin (FN), inhibit cell adhesion to FGF-2. Conv ersely, soluble FGF-2 prevents cell adhesion to VN but not FN, thus im plicating VN receptor in the cell-adhesive activity of FGF-2. Accordin gly, monoclonal and polyclonal anti-alpha(v) beta(3) antibodies preven t cell adhesion to FGF-2. Also, purified human alpha(v) beta(3) binds to immobilized FGF-2 in a cation-dependent manner, and this interactio n is competed by soluble VN but not by soluble FN. Finally, anti-alpha (v) beta(3) monoclonal and polyclonal antibodies specifically inhibit mitogenesis and urokinase-type plasminogen activator (uPA) up-regulati on induced by free FGF-2 in endothelial cells adherent to tissue cultu re plastic. These data demonstrate that FGF-2 interacts with alpha(v) beta(3) integrin and that this interaction mediates the capacity of th e angiogenic growth factor to induce cell adhesion, mitogenesis, and u PA up-regulation in endothelial cells.