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Effects of red wine polyphenols on postischemic neovascularization model in rats: low doses are proangiogenic, high doses anti-angiogenic

Celine Baron-Menguy^*, Arnaud Bocquet^*, Anne-Laure Guihot^*, Daniel Chappard, Marie-Joseph Amiot, Ramaroson Andriantsitohaina^*, Laurent Loufrani^* and Daniel Henrion^*,1

^* CNRS UMR 6214, Angers, France; INSERM UMR 771, Angers, France; Université d’Angers, UFR de Médecine, France;

INSERM, EMI 0335, Angers, France; and

UMR 476 INSERM/1260 INRA, Marseille, France

¹Correspondence: Department of Neurovascular Integrated Biology, UMR CNRS6214-INSERM771, Faculté de Médecine, 49045 Angers, France. E-mail: daniel.henrion{at}univ-angers.fr

Polyphenols, present in green tea, grapes, or red wine, have paradoxical properties: they protect against cardiac and cerebral ischemia but inhibit angiogenesis in vitro. So we investigated the effects of polyphenols in vivo on postischemic neovascularization. Rats treated with low (0.2 mg · kg^–1 · day^–1) or high (20 mg · kg^–1 · day^–1) doses of red wine polyphenolic compounds (RWPC) were submitted to femoral artery ligature on the left leg. Two wks after ligature, high doses of RWPC (i.e., 7 glasses of red wine) reduced arterial, arteriolar, and capillary densities and blood flow in association with an inhibition of a PI3 kinase-Akt-endothelial NO synthase (eNOS) pathway, decreased VEGF expression, and lower metalloproteinase (MMP) activation. Low doses of RWPC (i.e., 1/10th glass of red wine) increased the left/right (L/R) leg ratio to control level in association with an increased blood flow and microvascular density. This angiogenic effect was associated with an overexpression of PI3 kinase-Akt-eNOS pathway and an increased VEGF production without effect on MMP activation. Thus, low and high doses RWPC have respectively pro- and anti-angiogenic properties on postischemic neovascularization in vivo. This unique dual effect of RWPC offers important perspectives for the treatment and prevention of ischemic diseases (low dose) or cancer growth (high dose).—Baron-Menguy, C., Bocquet, A., Guihot, A.-L., Chappard, D., Amiot, M.-J., Andriantsitohaina, R., Loufrani, L., Henrion, D. Effects of red wine polyphenols on postischemic neovascularization model in rats: low doses are proangiogenic, high doses anti-angiogenic.

Key Words: VEGF • remodeling • nitric oxide • blood flow

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