Resveratrol Inhibits Angiogenic Response of Cultured Endothelial F-2 Cells to Vascular Endothelial Growth Factor, but Not to Basic Fibroblast Growth Factor

Resveratrol, a natural polyphenol in grapes, is known to prevent the cardiovascular diseases and to exert the antiangiogenic effect in in vivo models with vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF). We examined the effect of resveratrol on tubule formation of cultured endothelial F-2 cells. In collagen gel matrix, F-2 cells formed an extended network of tubular structures in response to VEGF or bFGF. Resveratrol dose-dependently prevented the VEGF-induced tubule formation, but failed to inhibit the angiogenic response to bFGF. We next examined whether the inhibition of nitric oxide (NO) production is linked to the antiangiogenic effect of resveratrol on VEGF-stimulated F-2 cells, because NO plays a crucial role in VEGF-induced tubular network formation. NO production was increased by VEGF, but not by bFGF, and resveratrol inhibited VEGF-stimulated NO production. N-G-nitro-L-arginine methyl ester (L-NAME) potently inhibited NO production under all conditions, including VEGF stimulation, and abrogated VEGF-induced tubule formation. However, L-NAME did not inhibit bFGF-induced tubule formation. To investigate the bFGF-induced in vivo antiangiogenic effect of resveratrol, we examined the effect of resveratrol on prostaglandin E-2 (PGE(2)) production and cyclooxygenase (COX) expression in NRK-F fibroblasts. COX-2 and its derived PGE(2) are important factors for bFGF-induced in vivo angiogenesis. Resveratrol dose-dependently prevented both COX-2 induction and PGE(2) production in bFGF-stimulated fibroblasts. These results suggest that resveratrol exerts the inhibitory effects on VEGF- and bFGF-induced angiogenesis through different mechanisms including inhibition of NO production in VEGF-stimulated endothelial cells and inhibition of COX-2 induction in bFGF-stimulated fibroblasts.