Problem Statement: Vascular brain lesions share pathological hallmarks with atherosclerosis, such as increased inflammation and oxidative stress. In addition, increasing evidence suggests an important role for oxidative stress in the pathogenesis and progression of hypertension with age via a decrease of NO production. These pathophysiological features are increased in older women because of menopause. Conversely, regular physical training has been shown to reduce these risk factors by upregulating antioxidant enzymatic systems and anti-inflammatory processes, which may slow down the usual increase in oxidative stress and inflammation during aging. However, the effect of regular physical activity and fitness level on cerebrovascular health is not well documented.The purpose of this research was i) to determine the beneficial effects of exercise on oxidative stress and inflammation in the brain using a mouse model of atherosclerosis associated with aging, ii) to test the impact of fitness status on enzymatic antioxidant efficiency, oxidative stress, and NO metabolism, and iii) to determine the associations among oxidative stress, and NO metabolism and cerebrovascular conductance (CVC) in postmenopausal women.Methods: For the animal study, 70 week old ApoE-/- mice under high fat – high cholesterol diet and C57Bl6 mice on a standard diet were divided into 4 groups: C57 and ApoE-/- exercise trained (ExT; cage with running wheel) and C57 and ApoE-/- untrained mice (UT; standard cage). Metabolic assessments (plasma cholesterol level and insulin tolerance) and brain imaging (gadolinium and USPIO contrast-enhanced MRI for blood brain barrier leakage and macrophages accumulation) were performed after 12 weeks of exercise training. After sacrificing the animals, lipid (malondialdehyde, MDA) and protein oxidation (advanced oxidation protein products, AOPP) and inflammation (TNFα and IL-1β) markers in the brain were assessed.For the human study, physical fitness, physical activity and resting CVC were measured in postmenopausal women (50 to 90 years). NO metabolites, lipid oxidation (MDA and 8-iso-prostaglandin F2α, F2-iso), DNA oxidation (8-hydroxy-2′-deoxyguanosine, 8OHdG), protein nitration (nitrotyrosine), antioxidant glutathione peroxidase, and catalase activities were measured in the plasma at rest.Results: In old ApoE-/- mice, 12 weeks of training was able to significantly reduce blood brain barrier leakage and brain macrophages accumulation (present in 71% of untrained vs. 14% of exercise trained ApoE-/- mice and not present in C57 mice). Similarly, exercise training decreased markers of oxidative stress (MDA: -43%, p<0.01, AOPP: -21%, p<0.05) and inflammation (TNFα: -17%, p<0.05 and IL-1β: -20%, p<0.05) in the brain of ApoE-/- mice. In parallel, exercise decreased insulin resistance and plasma cholesterol and significantly improved survival (77 vs. 49%, p<0.05).In postmenopausal women, we identified significant negative associations between oxidative stress and indices of physical fitness (MDA: r=-0.33, p<0.05; 8-iso-prostaglandin F2α: r=-0.39, p<0.05; 8OHdG: r=-0.35, p<0.05) and physical activity (MDA: r=-0.30, p<0.05; F2-iso: r=-0.41, p<0.01; 8-hydroxy-2′-deoxyguanosine: r=-0.39, p<0.05). Conversely, glutathione peroxidase was positively correlated with fitness level (r=0.55; p<0.01). Finally, CVC was significantly associated with 8OHdG (r=-0.36, p<0.05), nitrotyrosine (r=-0.32, p<0.05), and the end product of NO (r=0.44, p<0.01).Conclusion: The animal study demonstrated the occurrence of vascular brain damage in an aging model of atherosclerosis and showed that exercise training is able to partially reverse this outcome. In parallel, exercise decreased oxidative stress and inflammation directly in the brain.The human study findings demonstrated that, after menopause, fitness level and regular physical activity mediate against oxidative stress by maintaining antioxidant enzyme efficiency. Furthermore, these results suggest that oxidative stress and NO production modulate CVC.On the whole, these studies suggest that regular physical activity can improve neurovascular health of older women and animals through vascular function and inflammation. In addition, the decrease in oxidative stress resulting from this physical activity is likely involved as part of the underlying mechanisms.