P121	Chronic oral administration of red wine polyphenols prevents the angiotensin II-induced expression of pro-angiogenic factors, VEGF and MMP-2, in the rat aorta.
A.Walter, M.Sarr, A.Beretz, N.Etienne, V.Schini-Kerth
UMR CNRS 7034, Université Louis Pasteur de Strasbourg, Faculté de Pharmacie, Illkirch, FR.

Objectives: Epidemiological studies have indicated that regular intake of moderate amounts of red wine is associated with a reduced risk of mortality from coronary diseases and cancer. Angiogenesis is a key event controlling the development of atherosclerotic lesions and tumor growth. This process is controlled by several pro-angiogenic factors including matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF). The aim of the present study was to determine whether red wine polyphenols (RWPs) are able to prevent the expression of MMP-2 and VEGF in the arterial wall in response to chronic infusion of angiotensin II (Ang II). Methods: Male Wistar rats were infused for 14 days with different doses of Ang II (0.01, 0.1, 0.2 or 0.4 mg/kg/day). RWPs (150 mg/kg/day) were administered in the drinking water one week before the Ang II (0.4 mg/kg/day) infusion and thereafter throughout the Ang II treatment period. The expression level of VEGF and pro-MMP-2/MMP-2 was assessed in the aorta by immunohistochemistry and by Western blot analysis. MMP activity was determined in aortic sections by in situ zymography. Results : Immunohistochemical analysis of aortic sections indicated that infusion of Ang II to rats caused a dose-dependent increase in the expression levels of VEGF throughout the arterial wall (1.03, 1.73, 2.12 and 2.49-fold increase at 0.01, 0.1, 0.2 and 0.4 mg/kg/day Ang II, respectively, compared to the low basal VEGF level in aorta from control rats). A similar increase in VEGF protein level was observed in aortas by Western blot analysis. Ang II-treatment also increased the low basal level of pro-MMP-2/MMP-2 protein in a dose-dependent manner (the values were 0.9, 1.37, 1.62 and 2.18 at 0.01, 0.1, 0.2 and 0.4 mg/kg/day Ang II, respectively, compared to control rats). Increased pro-MMP-2/MMP-2 levels were associated with enhanced MMP activity in aorta. Chronic administration of RWPs totally prevented the expression of VEGF and pro-MMP-2/MMP-2 in aortas in response to the Ang II (0.4 mg/kg/day) treatment. Conclusions: The present findings indicate that infusion of Ang II to rats induces the expression of two major pro-angiogenic factors, VEGF and MMP-2, in the aortic wall. The stimulatory effect of Ang II is prevented by the chronic administration of RWPs in the drinking water. Thus, the anti-angiogenic properties of RWPs might delay the formation of new blood vessels and, hence, the development of atherosclerosis and tumor growth.

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