alphavbeta3 Integrin-dependent antiangiogenic activity of resveratrol stereoisomers.
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.
Belleri
Mirella
M
Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, Brescia, Italy.
Ribatti
Domenico
D
Savio
Monica
M
Stivala
Lucia Anna
LA
Forti
Luca
L
Tanghetti
Elena
E
Alessi
Patrizia
P
Coltrini
Daniela
D
Bugatti
Antonella
A
Mitola
Stefania
S
Nicoli
Stefania
S
Vannini
Vanio
V
Presta
Marco
M
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D002642:Chick Embryo; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D000077185:Resveratrol; D013237:Stereoisomerism; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D039302:Integrin alphaVbeta3; D013267:Stilbenes; D000077185:Resveratrol