Abstract P141: Aging in Mice Enhances Microvascular Reactive Oxygen Species (ROS) That Impair the Anti-Contractile Actions of Perivascular Adipose Tissue (PVAT)

Background: Reactive oxygen species (ROS) contribute to oxidative stress and aging that predicts cardiovascular disease (CVD). Perivascular adipose tissue (PVAT) enhances endothelial function and reduces contractility of normal vessels. We tested the hypothesis that ROS and age impair PVAT signaling using mesenteric arterioles (MAs) from young and old wild type (Wt) and superoxide dismutase 3 knockout mice (KO). Methods and Results: MAs were isolated with and without PVAT from young (3 – 4 months; n = 5 – 7) and old (23 – 24 months; n = 5 – 7) wild-type (Wt) and superoxide dismutase 3 knockout (-/-) mice (to create oxidative stress). Contractions were assessed on an isometric myograph and ROS and mitochondrial ROS by fluorescence microscopy in MAs loaded with dihydroethidium or MitoSOX Red. The increase in ROS and mitochondrial ROS signals with 10 -7 mol·l -1 endothelin 1 (ET1) were increased in MAs from Wt old vs young mice (0.21 ± 0.05 vs 0.11 ± 0.04 units; P<0.05 and 0.15 ± 0.04 vs 0.08 ± 0.04 units; P<0.05 respectively). Amongst Wt mice, the effect of PVAT to reduce contractions to 10 -6 mol·l -1 U-46,619 was reduced in old vs young mice (15 ± 1 vs 45 ± 6% reduction; P<0.005) with similarly reduced effects of PVAT in vessels from old mice on contractions to 10 -7 mol·l -1 endothelin 1 (ET1: 15 ± 4 vs 34 ± 3% reduction; P<0.005). Compared to young Wt mice, MAs from young SOD3 -/- mice had reduced protection by PVAT from contractions to U-46,619 (25 ± 3 vs 45 ± 6% reduction; P<0.01) or to ET1 (3 ± 2 vs 34 ± 8% reduction; P<0.005). The effects of oxidative stress to lessen the protective effects of PVAT were lessened in old mice where the reductions in contractions mediated by PVAT to U-46,619 were no longer different in SOD +/+ vs -/- mouse MAs (12 ± 1 vs 15 ± 1% reduction; NS) while contractions to ET1 remained somewhat protected by PVAT (8 ± 2 vs 15 ± 4% reduced; P<0.05). Conclusions: Aging enhances ROS generation by mesenteric arterioles that impairs the beneficial effects of PVAT to protect vessels from contractions with thromboxane and endothelin. This discloses a novel mechanism for age-related cardiovascular disease.