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Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy (M.B., S.N., M.P.); Department of Human Anatomy and Histology, University of Bari, Bari, Italy (D.R.); Department of Biology, University of Milan, Milan, Italy (F.C.); Department of Chemistry, University of Modena and Reggio Emilia, Modena, Italy (L.F.); and Unit of General Pathology, Department of Experimental Medicine, University of Pavia, Pavia, Italy (V.V., L.A.S.)
Abstract
Neovascularization plays an important role in neoplasia and angioproliferative diseases. Two major modalities have been developed so far to affect neovascularization: its prevention by antiangiogenic compounds, and immature vessel disruption by vascular-targeting agents. trans-Resveratrol, found in grapes and wine, exerts antioxidant, antineoplastic, and antiangiogenic activities. Here, among various synthetic trans-resveratrol derivatives tested, 3,5,4'-trimethoxystilbene was an antiangiogenic agent 30 to 100 times more potent than parent compound in inhibiting endothelial cell proliferation, sprouting, collagen gel invasion, and morphogenesis (ID50 = 0.3–3.0 µM). In addition, 3,5,4'-trimethoxystilbene acts as a vascular-targeting agent by causing microtubule disassembling and tubulin depolymerization and by impairing the repositioning of the microtubule organization center and the formation of membrane ruffles in migrating endothelial cells. In keeping with a vascular-targeting ability, 3,5,4'-trimethoxystilbene induced apoptosis only in subconfluent endothelial cells and apoptotic regression of immature vessels in the ex vivo rat aorta ring assay. In vivo, 3,5,4'-trimethoxystilbene caused the rapid stasis of blood flow and regression of intersegmental vessels in the trunk of zebrafish embryos. In addition, it inhibited blood vessel growth and caused the disappearance of pre-existing blood vessels in the area vasculosa of the chick embryo. In conclusion, 3,5,4'-trimethoxystilbene associates an antiangiogenic profile to a significant vascular-targeting activity.
Address correspondence to: Dr. Marco Presta, General Pathology, Dept. Biomedical Sciences and Biotechnology, Viale Europa 11 25123 Brescia, Italy. E-mail: presta{at}med.unibs.it
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