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Upregulation of TSP‐1 Expression Associates with Enhanced Phenotypic Switching of Vascular Smooth Muscle Cells in KKAy+/− Mice, A Mouse Model of Metabolic Syndrome

Metabolic syndrome (MetS) refers to a constellation of risk factors that include insulin resistance, abdominal obesity, hyperglycemia, hypertension and dyslipidemia. Atherosclerotic complications are the leading cause of increased morbidity and mortality in MetS. Individuals with MetS have an increased propensity for abnormal migration and proliferation of vascular smooth muscle cells (VSMCs), a key step responsible for development and progression of atherosclerosis. We previously reported that high glucose and high leptin concentrations, characteristic of MetS, upregulate the expression of a potent proatherogenic matricellular protein thrombospondin‐1 (TSP‐1) in human and mouse aortic smooth muscle cells. Multiple epidemiological and animal studies document an important role of TSP‐1 in development of atherosclerosis. TSP‐1 expression is significantly elevated in both diabetic and obese patients and animal models. Previous studies suggest that TSP‐1 stimulates VSMC migration and proliferation which may contribute to accelerated atherosclerotic and restenotic complications. The goal of the present study was to investigate whether upregulation of TSP‐1 expression correlates with enhanced VSMC phenotypic switching in the agouti yellow KKAy+/− mice, a mouse model of MetS characterized by hyperglycemia, obesity and hyperleptinemia. Briefly, yellow obese, hyperglycemic KKAy+/− mice and age‐matched black lean, non‐hyperglycemic littermates (KKAy−/−), weaned at 4 wks of age were maintained on regular chow diet until 24 wks of age (study endpoint). After an overnight fasting, mice were euthanized at endpoint to harvest blood and aortic vessels; plasma samples were processed for lipid measurements and aortic tissue lysates were subjected to immunoblotting. Yellow KKAy+/− mice showed a significant increase in body weight, blood glucose, total cholesterol and total triglyceride levels as compared to black KKAy−/− littermate mice. Immunoblotting of aortic tissue lysates revealed an upregulation of TSP‐1 expression concomitant to increased expression of PCNA (proliferation marker) in obese KKAy+/− mice as compared to age‐matched lean KKAy−/− littermates. There was an increased expression of vimentin (synthetic SMC marker) coupled with reduced SM‐MHC (contractile SMC marker) expression in the aortic vessels of obese KKAy+/− mice as compared to the lean KKAy−/− mice. Finally, immunoblotting experiments further demonstrated increased activation of ERK‐1/2 and p38‐MAPK, signaling mediators of VSMC growth, in aortic vessels of obese KKAy+/− mice as compared to lean KKAy−/− littermates. Taken together, our data suggest a potential link between TSP‐1 and VSMC phenotypic transition that may contribute to atherosclerotic complications associated with metabolic syndrome.