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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1522.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

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

Paola Haddad; Sylvie Dussault; Jessika Groleau; Julie Turgeon; Sophie-Elise Michaud; Catherine Ménard; Gemma Perez; Fritz Maingrette; Alain Rivard

From the Department of Cardiovascular Research, Centre Hospitalier de l’Université de Montréal, Québec, Canada.

Correspondence to Alain Rivard, MD, Centre Hospitalier de l’Université de Montréal, 1560 Sherbrooke Est, Montreal, Que, H2L 4M1. E-mail rivardal{at}total.net

Objective— Because Nox2-containing NADPH oxidase is a major source of ROS in the vasculature, we investigated its potential role for the modulation of ischemia-induced neovascularization in conditions of increased oxidative stress.

Methods and Results— To mimic a clinical situation of increased oxidative stress, mice were exposed to cigarette smoke before and after the surgical induction of hindlimb ischemia. Nox2 expression and oxidative stress in ischemic tissues were significantly increased in wild-type mice, but not in mice deficient for the Nox2-containing NADPH oxidase (Nox2^–/–). Nox2^–/– mice demonstrated faster blood flow recovery, increased capillary density in ischemic muscles, and improved endothelial progenitor cell functional activities compared to Nox2^+/+ mice. In addition, Nox2 deficiency was associated with increased antioxidant and nitrite concentrations in plasma, together with a preserved expression of eNOS in ischemic tissues. In vitro, Nox2^–/– endothelial cells exhibit resistance against superoxide induction and improved VEGF-dependent angiogenic activities compared to Nox2^+/+ endothelial cells. Importantly, the beneficial effects of Nox2 deficiency on neovascularization in vitro and in vivo were lost after treatment with the NO inhibitor L-NAME.

Conclusions— Nox2-containing NADPH oxidase deficiency protects against ischemia in conditions of increased oxidative stress. The mechanism involves improved neovascularization through a reduction of ROS formation, preserved activation of the VEGF/NO angiogenic pathway, and improved functional activities of endothelial progenitor cells.

In a clinical situation of increased oxidative stress (exposure to cigarette smoke), Nox2-containing NADPH oxidase deficiency is associated with improved neovascularization after hindlimb ischemia. The mechanisms involved include reduced ROS formation, preserved activation of the VEGF/NO angiogenic pathway, and improved functional activities of endothelial progenitor cells.

Key Words: NADPH oxidase • neovascularization • cigarette smoking • nitric oxide • endothelial progenitor cells