Abstract P128: Sexual Dimorphisms In Perivascular Adipose Tissue In A Novel Mouse Model Of Diet-Induced Metabolic Syndrome.

Abstract

Metabolic syndrome (MetS) is a complex multifactorial disease that increases cardiovascular risk. Vascular dysfunction associated with MetS is strongly influenced by perivascular adipose tissue (PVAT) which acts as a reservoir for immune cells. Sexual dimorphisms of PVAT pathophysiology are poorly understood due to a lack of clinically relevant animal models of MetS that show metabolic disturbances in males and females. Using a new diet-induced model of MetS pathophysiology in both sexes, we characterised the aortic leukocyte profile and determined PVAT influence on vascular function. Six-week-old male and female C57BL/6 mice were fed either a high-fat diet (43% kcal) with high sugar and salt (10% high fructose and 0.9% NaCl; HFSS) in drinking water, or normal control diet (NCD) for 10 weeks. Physiological parameters were measured fortnightly. At endpoint, aorta with PVAT intact was isolated for leukocyte enumeration (flow cytometry) or for in vitro vascular reactivity (± PVAT; wire myography). Weight gain (NCD M: 29.3±0.5 g vs. MetS M: 37.5±1.0 g; NCD F: 23.6±0.7 g vs. MetS F: 28.9±1.2 g), fasting blood glucose (NCD M: 9.5±0.4 mmol/L vs. MetS M: 11.3 mmol/L; NCD F: 8.9±0.3 mmol/L vs. 10.4±0.5 mmol/L), blood cholesterol (NCD M: 125.0±3.0 mg/dL vs. MetS M: 177.5±6.5 mg/dL; NCD F: 96.7±2.9 mg/dL vs. MetS F: 130.7±3.4 mg/dL) and systolic blood pressure (NCD M: 121.0±1.8 mmHg vs. MetS M: 132.0±2.1 mmHg; NCD F: 122.3±2.2 mmHg vs. MetS F: 133.6±2.7 mmHg) were increased in both sexes of HFSS-fed mice (P<0.05 n= 12; vs. NCD) confirming that the HFSS model is a clinically relevant diet-induced model of MetS. Despite comparable metabolic disturbances in both sexes, aortic inflammation was only observed in males (increased pro-inflammatory monocytes (Ly6C hi+ ; M: 3.3±0.5 x 10 3 cells/aorta vs F: 1.6±0.4 x 10 3 cells/aorta) and neutrophils (Ly6G + ; M: 0.9±-0.2 x 10 3 cells/aorta vs F: 0.3+/0.1 x 10 3 cells/aorta); P<0.05 vs. HFSS-fed female. MetS altered PVAT and vascular function in both sexes, but with contrasting effects. PVAT blunted endothelium-dependent relaxation in HFSS-fed males (P<0.05 vs. NCD male) and in NCD-fed females (P<0.05 vs. HFSS females). The data indicates that sexual dimorphisms in PVAT impacts MetS-induced aortic inflammation and endothelial dysfunction.