alfa-v-beta-3 Integrin-dependent antiangiogenic activity of resveratrol stereoisomers

Angiogenesis is target for antineoplastic and chemopreventivetherapies. The natural phytoalexin resveratrolis 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 interactwith the B3 integrin subunit, raising the possibility thatinhibition of endothelial AvB3 integrin function may concurto its angiosuppressive activity. To get novel insightsabout the antiangiogenic activity of resveratrol, we comparedcis- and trans-resveratrol stereoisomers for theireffect on the angiogenesis process and endothelial AvB3integrin function. trans-Resveratrol inhibits endothelialcell proliferation and the repair of mechanically woundedendothelial cell monolayers. Also, it prevents endothelialcell sprouting in fibrin gel, collagen gel invasion, andmorphogenesis on Matrigel. In vivo, trans-resveratrolinhibits vascularization of the chick embryo area vasculosaand murine melanoma B16 tumor growth and neovascularization.In all the assays, cis-resveratrol exerts a limited, if any, effect. In keeping with these observations, transresveratrol,but not cis-resveratrol, inhibits AvB3 integrindependentendothelial cell adhesion and the recruitmentof enhanced green fluorescent protein-tagged B3 integrinin focal adhesion contacts. In conclusion, stereoisomeryaffects the antiangiogenic activity of resveratrol, the transisomer being significantly more potent than the cis isoform.The different antiangiogenic potential of resveratrolstereoisomers is related, at least in part, to theirdifferent capacity to affect AvB3 integrin function. Thismay have profound implications for the design of syntheticantiangiogenic/angiopreventive phytoalexin derivatives.