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Inhibition of Vascular Endothelial Growth Factor-Induced Angiogenesis by Resveratrol through Interruption of Src-Dependent Vascular Endothelial Cadherin Tyrosine Phosphorylation

Departments of Surgery (M.-T.L.) and Obstetrics and Gynecology (M.-L.Y.), National Taiwan University Hospital, Taipei, Taiwan; Departments of General Medicine and Obstetrics and Gynecology (M.-L.Y.) and Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology (C.Y.L., M.-L.K.), College of Medicine, National Taiwan University, Taipei, Taiwan

Resveratrol, a polyphenolic compound found in grapes and other fruits, has been reported to inhibit angiogenesis with an as yet elusive mechanism. Here, we investigate the detailed mechanism by which resveratrol inhibits vascular endothelial growth factor (VEGF)-induced angiogenic effects in human umbilical endothelial cells (HUVECs). Exposure of HUVECs to 1 to 2.5 µM resveratrol significantly blocked VEGF-mediated migration and tube formation but not cell proliferation. Under the same concentrations, resveratrol failed to affect VEGF-stimulated activation of VEGF receptor, extracellular signal-regulated protein kinase 1/2, p38 mitogen-activated protein kinase, and Akt. Of interest, resveratrol, at the dose of 1 or 2.5 µM, effectively abrogated VEGF-mediated tyrosine phosphorylation of vascular endothelial (VE)-cadherin and its complex partner, -catenin. This inhibitory effect of resveratrol reflected on the retention of VE-cadherin at cell-cell contacts as demonstrated by immunofluorescence. Src kinase assay showed that VEGF-induced endogenous Src kinase activation was strongly inhibited by 1 and 2.5 µM resveratrol. Supportively, inhibition of Src activity by overexpression of Csk resulted in attenuation of the tyrosine phosphorylation of VE-cadherin and endothelial cell (EC) tube formation. Again, transfection with v-Src, an active form of Src, could reverse resveratrol inhibition of VE-cadherin tyrosine phosphorylation and EC tube formation. Reactive oxygen species (ROS) has been shown to be involved in VE-cadherin phosphorylation and its related functions. Flow cytometric analysis showed that VEGF stimulated an evident increase of peroxide, which was strongly attenuated by resveratrol. In addition, antioxidant N-acetyl-cysteine was demonstrated to strongly inhibit VEGF-mediated Src activation, VE-cadherin tyrosine phosphorylation, and HUVEC tube formation. Together, our data suggest that resveratrol inhibition of VEGF-induced angiogenesis was mediated by disruption of ROS-dependent Src kinase activation and the subsequent VE-cadherin tyrosine phosphorylation.

Received April 10, 2003; accepted July 18, 2003.

Address correspondence to: Dr. Min-Liang Kuo, Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Rd., Taipei. E-mail: toxkml{at}ha.mc.ntu.edu.tw

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