Resveratrol modulates angiogenesis through the GSK3β/β-catenin/TCF-dependent pathway in human endothelial cells

Vascular endothelial growth factor (VEGF) plays a critical role in angiogenesis due to its potent and specific ability to promote the proliferation and migration of endothelial cells. Resveratrol has been shown to have many health-benefiting effects, including the protection of cardiovascular system. In this study we examined the effect of resveratrol on angiogenesis in human umbilical vein endothelial cells (HUVECs). We observed that resveratrol was able to modulate the expression of VEGF and the formation of vascular network in a biphasic pattern. While resveratrol at low concentrations, from 1 to 10μM, up-regulated the expression of VEGF and promoted angiogenesis, it had opposite effect at high concentrations (20μM and higher). The biphasic effect of resveratrol on angiogenesis was confirmed by chick chorioallantoic membrane assay. Up-regulation of VEGF expression depended on the nuclear accumulation and transcriptional activity of β-catenin. Correspondingly, GSK3β, a negative regulator of β-catenin, turned into a less active state (phosphorylated at Ser9) in cells exposed to 5μM of resveratrol, but became more active at 20μM. We demonstrated that both Akt and ERK signaling pathways, which are known to be critical for angiogenesis, became activated in response to 5μM of resveratrol and functioned to inactivate GSK3β. Our findings may have implications in the management of cardiovascular diseases and other conditions such as cancer by the use of resveratrol.