FIBROBLAST GROWTH FACTOR-2 (FGF-2) INDUCES VASCULAR ENDOTHELIAL GROWTH-FACTOR (VEGF) EXPRESSION IN THE ENDOTHELIAL-CELLS OF FORMING CAPILLARIES - AN AUTOCRINE MECHANISM CONTRIBUTING TO ANGIOGENESIS

FGF-2 and VEGF are potent angiogenesis inducers in vivo and in vitro, Here we show that FGF-2 induces VEGF expression in vascular endothelia l cells through autocrine and paracrine mechanisms. Addition of recomb inant FGF-2 to cultured endothelial cells or upregulation of endogenou s FGF-2 results in increased VEGF expression, Neutralizing monoclonal antibody to VEGF inhibits FGF-2-induced endothelial cell proliferation , Endogenous 18-kD FGF-2 production upregulates VEGF expression throug h extracellular interaction with cell membrane receptors; high-M-r FGF -2 (22-24-kD) acts via intracellular mechanism(s). During angiogenesis induced by FGF-2 in the mouse cornea, the endothelial cells of formin g capillaries express VEGF mRNA and protein. Systemic administration o f neutralizing VEGF antibody dramatically reduces FGF-2-induced angiog enesis. Because occasional fibroblasts or other cell types present in the corneal stroma show no significant expression of VEGF mRNA, these findings demonstrate that endothelial cell-derived VEGF is an importan t autocrine mediator of FGF-2-induced angiogenesis, Thus, angiogenesis in vivo can be modulated by a novel mechanism that involves the autoc rine action of vascular endothelial cell-derived FGF-2 and VEGF.