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.