Abstract 429: Reactive Oxygen Species Impair Endothelial Function and Perivascular Adipose Tissue Signaling in Mesenteric Arterioles From Ovariectomized Rats

Abstract

Perivascular adipose tissue (PVAT) normally promotes vascular endothelium dependent relaxation (EDRs), whereas reactive oxygen species (ROS) impair endothelial function. However, the effects of the menopause on PVAT, and its interaction with ROS, are unexplored. We tested the hypothesis that ovariectomy (OVX) causes oxidative stress that impairs microvascular PVAT signaling. Mesenteric arterioles (MAs) were isolated from rats 4-6 weeks after sham-operation (Sham) or OVX. Alternate rats received vehicle or tempol (2mmol · 1 -1 of water) throughout (n=6/group). MAs were preconstricted with 10 -7 M norepinephrine for measurement of acetylcholine (ACh)-induced endothelial derived relaxation (EDR), endothelium derived relaxation factor (EDRF) and NO activity (DAF-FM fluorescence) using a Mulvany-Halperin wire myograph and fluorescence RatioMaster system. Other vessels were studied under spontaneous tone with dilator pathways blocked with 10 -4 M L-NAME, 10 -5 M apamine and 10 -6 M charybdotoxin to measure ACh-induced endothelium dependent contraction factor (EDCF) and ROS generation (temp-9AC fluorescence). OVX rats had vascular remodeling (midia: lumen diameter: 4.4± 0.4 vs 1.5 ± 0.3 μm·μm -1 , P<0.01). Their MAs without PVAT had diminished EDR (48 ±5 vs 73±3%; P<0.05), EDRF (20±4 vs 41±4%; P<0.01) and NO activity (0.4 ± 0.1 vs 0.7± 0.1 units; P<0.05) and developed an EDCF (23±6 vs 5±3%; P<0.05) and ACh-induced ROS (0.5±0.1 vs 0.1±0.0 units; P<0.01). The presence of PVAT surrounding Sham vessels enhanced EDR (90±3 vs 73±3%; P<0.05), EDRF (57±3 vs 41±3%; P<0.05) and NO (1.2±0.01 vs 0.7±0.1 units; P<0.05). All of these beneficial effects of PVAT were lost in OVX rats. Four to six weeks of tempol drinking in OVX rats restored normal intrinsic vascular endothelial function and NO and restored all the beneficial effects of PVAT while preventing microvascular remodeling. In conclusion, OVX rats had microvascular remodeling and severe endothelial dysfunction ascribed to intrinsic vascular effects of ROS that summated with ROS-dependent interruption of a beneficial microvascular PVAT signaling pathway. Thus, therapeutic targets for menopausal vascular dysfunction should be expanded to include ROS and its extravascular actions on PVAT.