Abstract 19716: Role of Aldose Reductase in Perivascular Adipose Tissue and Vascular Dysfunction in Short-Term Diet-Induced Obesity

Abstract

Obesity is a risk factor for diabetes and cardiovascular (CVD) disease, and the quantity of perivascular adipose tissue (PVAT) associates with CVD risk. To test the hypothesis that changes in PVAT are causal in diet-induced vascular dysfunction, mice (wild type, WT and aldose reductase-null, ARKO, an obesity-sensitive model) were fed a low fat chow diet (10% kcal fat) or high fat chow diet (HFD; 60% kcal fat) for 4 weeks (short-term) in either 8 weeks old or 18 weeks old C57 mice (n=4-6/group). After 4 weeks, body weight and lean and fat mass was measured (DexaScan). Vascular, endothelial and PVAT function and structure were measured in isolated thoracic aorta without and with PVAT in response high potassium solution (100 mM HIK), phenylephrine (PE), acetylcholine (ACh), thromboxane A2 analog (U46619) and sodium nitroprusside (SNP). As expected, HFD increased body weight in all groups although ARKO mice (young and old) gained significantly more body weight, fat grams (whole body, epididymal), and % body fat when compared with age-matched WT mice. Similarly, aortic PVAT mass increased in ARKO mice indicating that PVAT growth mirrored visceral adiposity induced by short-term HFD feeding and enhanced in ARKO mice. PVAT significantly enhanced HIK-induced contractions and SNP-stimulated relaxations (%), decreased U46619-induced tension but neither altered PE-stimulated contraction nor ACh-induced relaxation (%) in isolated aorta of LFD-fed WT. Several of these PVAT effects were altered by age, AR deletion and 4-weeks of HFD feeding. For example, PVAT rescued endothelial dysfunction (ACh, -84.0±7.7%) detected as decreased ACh-induced relaxation in aorta without PVAT (ACh, -43.6±6.8%, p<0.05) of 22-week WT mice fed HFD, indicating that short-term HFD induces compensatory PVAT changes that counteract deleterious endothelium changes -- a novel finding. Effects of PVAT were only slightly modified in ARKO mice despite a greater mass of PVAT, indicating a complicated role of AR deletion in PVAT. These data add to a growing literature that reveals a complex, integrative vascular function of PVAT that is modulated during obesity and metabolic syndrome.