Abstract 204: Sex-specific Differences In The Role Of TSP1 On Metabolic Syndrome-induced Atherosclerosis

Abstract

Metabolic syndrome (MetS) amplifies risks of atherosclerotic complications. MetS induces abnormal vascular smooth muscle cell (VSMC) migration and proliferation, hallmark of SMC de-differentiation, crucial in the pathogenesis of atherosclerosis. Despite multiple studies revealing sexual dimorphism in atherosclerosis, underlying sex-specific mechanisms are poorly understood. We previously reported a protective role of a potent proatherogenic protein, thrombospondin-1 (TSP1), in hyperglycemia- or hyperleptinemia-induced atherosclerosis. The goal of the present study was to interrogate sex-specific differences in the role of TSP1 on MetS-induced atherosclerosis. We generated a mouse model of combined MetS and atherosclerosis (KKAy +/- ApoE -/- ) by crossing obese hyperglycemic agouti KKAy +/- mice with atherosclerotic ApoE -/- . Male and female age-matched MetS KKAy +/- ApoE -/- and non-MetS KKAy -/- ApoE -/- mice were placed on standard lab diet from 4-24 wks age. After overnight fasting, mice were harvested; plasma, aorta and heart were collected for various studies. In male MetS KKAy +/- ApoE -/- , increased aortic root ORO-positive lipid burden, reduced LMOD (SM contractile marker) and SRF (transcriptional activator of SM differentiation) expression in aortic vessels associated with augmented TSP1 expression vs. non-MetS KKAy -/- ApoE -/- mice. In contrast, no significant differences in lesion lipid burden, TSP1, LMOD and SRF expression were detected between the female genotypes. To delineate whether TSP1 plays a direct role in SMC de-differentiation in MetS, we next crossed KKAy +/- with TSP1 -/- to generate MetS mice with and without global TSP1 deletion. Male and female KKAy +/- TSP1 +/+ (with intact TSP1) and KKAy +/- TSP1 -/- (lacking TSP1) on standard lab diet from 4-18 wks age were harvested at endpoint for aortic tissue collection. In male KKAy +/- TSP1 -/- aortic vessels, SM contractile marker expression (LMOD, calponin) was markedly increased vs. KKAy +/- TSP1 +/+ , suggesting reduced SMC de-differentiation. In contrast, TSP1 deletion had no effect on SM contractile marker expression in female MetS KKAy +/- . Together, these data suggest a sex-specific role of TSP1 on SMC de-differentiation and atherosclerotic lesion formation in MetS.