P752Sex-associated differences in oxidative stress and renin-angiotensin system contribute to a differential regulation of vascular aging

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Abstract

Aging is a cardiovascular risk factor associated to an increase of reactive oxygen species (ROS) and Renin-Angiotensin System (RAS) activation, which in turn contributes to vascular dysfunction and remodelling. Both systems are known to be influenced by sex. In this regard, our study aims to determine whether sex-associated differences in ROS and RAS contribute to a differential regulation of vascular aging and associated dysfunction. Male and female outbreed CD-1 mouse were studied at 3, 7 and 12 months of age (mo). To determine the contribution of RAS, mice were treated from 3 to 12 months with Losartan (0.6 mg/L in the drinking water). Contraction to KCl and Angiotensin II (AngII) were determined in aortic rings by wire-myography. Morphometric analysis was performed by Haematoxylin-eosin staining. Oxidative stress was determined in aortic cross sections by dihydroethidiem (DHE). Sections were treated with AngII (10-6M), apocynin (10-4M), L-NMMA (3x10-4M) to determine signalling pathways involved in ROS production. At 12 mo, contractions to 60mM KCl were higher in males (15.4±0.4 mN) than in females (12.6±0.5 mN); P<0.001. Aging also increases AngII contractions at higher levels in 12mo males (AUC: 84.3±19.1) compared to 12mo females (AUC: 34.5±9.8); P<0.05. Losartan treatment prevented age-related increase in KCl contractions, with higher effect in females (P<0.01) than in males (P<0.05). Aging also triggers an outward hypertrophy of aorta [Wall Thickness (μm): 3mo (Male: 54.5±4.9 vs Female 47.0±7.3); 12mo (Male 101.4±4.3 vs Female 100.3±3.4); P<0.001], which appears at earlier age (7mo) in males (93.1±2.5) than in females (78.6±3.1), P<0.05. Losartan treatment prevented hypertrophy in both males and females (P<0,001). Aging-associated increase of ROS follows same chronology as vascular hypertrophy [DHE Fluorescence (%): 3mo (Male 35.3±8.7 vs Female 30.5±5.0); 7 mo (Male 58.7±3.3 vs Female 31.6±5.5); 12mo (Male 72.69±2.6 vs Female 69.1±4.3); P<0.001], although losartan did not modify ROS generation in 12mo mice. Neither we found changes in ROS generation in sections treated with AngII, suggesting a lack of crosstalk between RAS and ROS in vascular aging. On the other hand, apocynin treatment diminished ROS generation in 12 mo female (P<0.01) and in 7mo and 12mo males (P<0.01). Aging increases vascular contraction and induces outward hypertrophy in a different time-course in males and females. Sex-associated differences in RAS activity with aging are also observed. Although RAS plays a critical role in the aging-associated hypertrophy, it does not contribute to the increased ROS generation observed.

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