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

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).