Moderate consumption of red wine (cabernet sauvignon) improves ischemia‐induced neovascularization in ApoE‐deficient mice: effect on endothelial progenitor cells and nitric oxide

Abstract

Moderate consumption of red wine is associated with a decreased incidence of cardiovascular diseases in populations with relatively high amount of fat in the diet. However, the mechanisms involved in this protective effect are not completely understood. Here we show that moderate consumption of red wine (equivalent to 2 glasses/day in humans) but not ethanol only, improves blood flow recovery by 32% after hindlimb ischemia in hypercholesterolemic ApoE-deficient mice. In ischemic tissues, red wine consumption reduces oxidative stress and increases capillary density by 46%. Endothelial progenitor cells (EPCs) have been shown to have an important role in postnatal neovascularization. We found that the number of EPCs is increased by 60% in ApoE mice exposed to red wine. Moreover, the migratory capacity of EPCs is significantly improved in red wine-drinking mice. The wine used in our study is a cabernet sauvignon from Languedoc-Roussillon, France, which contains a relatively high concentration (4-6 mg/L) of the polyphenolic antioxidant resveratrol. We demonstrate that resveratrol can rescue oxidized low-density lipoprotein (oxLDL)-induced impairment of in vitro angiogenic activities in human umbilical vein endothelial cells (HUVECs). Resveratrol exposure is also associated with increased activation of Akt/eNOS together with a restoration of nitric oxide production in HUVECs exposed to oxLDL. Our study suggests that moderate consumption of red wine improves ischemia-induced neovascularization in high-cholesterol conditions by increasing the number and the functional activities of EPCs and by restoring the Akt-eNOS-NO pathway.

Nox2-Containing NADPH Oxidase Deficiency Confers Protection From Hindlimb Ischemia in Conditions of Increased Oxidative Stress

“…We and others have previously shown that situations of excessive oxidative stress can impair VEGF-induced angiogenesis in endothelial cells. 17,18,25 Here we found that mature endothelial cells isolated from Nox2 Ϫ/Ϫ mice exhibit lower superoxide levels after CSE exposure. Moreover, reduced superoxide production in Nox2 Ϫ/Ϫ endothelial cells exposed to CSE was associated with improved cellular migration and tube formation in response to VEGF.…”

“…14 To evaluate local oxidative stress levels in ischemic muscles, nitrotyrosine immunostaining (Upstate) and dihydroethidium staining (DHE, Molecular Probes) were used. 25 …”

“…EPCs were isolated from the femora and tibiae by flushing the bone marrow cavities using culture medium as previously described. 25 Bone marrow EPCs were characterized as adherent cells that were positive for both DiI-acLDL uptake and lectin binding. 25 …”

“…25 Bone marrow EPCs were characterized as adherent cells that were positive for both DiI-acLDL uptake and lectin binding. 25 …”

“…4 -6 Although EPCs have been shown to express higher levels of antioxidative enzymes and enhanced protection against oxidative stress compared to mature endothelial cells, 31 recent studies have indicated that EPCs are sensitive to oxidative stress. 25,32 In the context of cigarette smoking, ROS formation is significantly increased in EPCs whereas the plasma antioxidant level of smokers is reduced and correlates with impaired EPC number and functional activity. 26 In contrast to previous reports in humans, 26,33 we did not document any significant effect of cigarette smoke exposure on the absolute number of mouse peripheral blood EPCs in the current study.…”