Abstract
Angiogenesis is target for antineoplastic and chemopreventive therapies. The natural phytoalexin resveratrol is found in grapes and red wine as cis and trans stereoisomers. trans-Resveratrol shows antiangiogenic activity, but its mechanism of action is not fully elucidated. Recently, trans-resveratrol has been shown to interact with the beta3 integrin subunit, raising the possibility that inhibition of endothelial alphavbeta3 integrin function may concur to its angiosuppressive activity. To get novel insights about the antiangiogenic activity of resveratrol, we compared cis- and trans-resveratrol stereoisomers for their effect on the angiogenesis process and endothelial alphavbeta3 integrin function. trans-Resveratrol inhibits endothelial cell proliferation and the repair of mechanically wounded endothelial cell monolayers. Also, it prevents endothelial cell sprouting in fibrin gel, collagen gel invasion, and morphogenesis on Matrigel. In vivo, trans-resveratrol inhibits vascularization of the chick embryo area vasculosa and murine melanoma B16 tumor growth and neovascularization. In all the assays, cis-resveratrol exerts a limited, if any, effect. In keeping with these observations, trans-resveratrol, but not cis-resveratrol, inhibits alphavbeta3 integrin-dependent endothelial cell adhesion and the recruitment of enhanced green fluorescent protein-tagged beta3 integrin in focal adhesion contacts. In conclusion, stereoisomery affects the antiangiogenic activity of resveratrol, the trans isomer being significantly more potent than the cis isoform. The different antiangiogenic potential of resveratrol stereoisomers is related, at least in part, to their different capacity to affect alphavbeta3 integrin function. This may have profound implications for the design of synthetic antiangiogenic/angiopreventive phytoalexin derivatives.
Highlights
Angiogenesis is a multistep process that begins with the degradation of the basement membrane by activated endothelial cells that will migrate and proliferate, leading to the formation of solid endothelial cell sprouts into the stromal space
The results show that trans-resveratrol is significantly more potent than the cis isomer in inhibiting different steps of the angiogenesis process in vitro and tumor growth and neovascularization in vivo
Similar results were obtained in murine aortic endothelial cells (MAEC) and Bovine aortic endothelial cells (BAEC) stimulated by serum, in FGF2T-MAECs stimulated by endogenous overexpressed fibroblast growth factor 2 (FGF2) [24], and in Human umbilical vein endothelial cells (HUVEC) stimulated by angiogenic growth factor-enriched medium
Summary
Angiogenesis is a multistep process that begins with the degradation of the basement membrane by activated endothelial cells that will migrate and proliferate, leading to the formation of solid endothelial cell sprouts into the stromal space. Vascular loops are formed and capillary tubes develop with formation of interendothelial tight junctions and deposition of new basement membrane [1]. Antiangiogenic compounds may act as cancer chemopreventive drugs, the so-called ‘‘angiopreventive’’ agents [5, 6]. To this respect, dietary phytochemicals derived from edible plants may represent a promising class of compounds [7]
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