Sex-specific differences in atherosclerosis, thrombospondin-1, and smooth muscle cell differentiation in metabolic syndrome versus non-metabolic syndrome mice

• Published in: Frontiers in cardiovascular medicine 2022-11, Vol.9, p.1020006-1020006
• Main Authors: Gupta, Shreya, Khanal, Saugat, Bhavnani, Neha, Mathias, Amy, Lallo, Jason, Kiriakou, Ariana, Ferrell, Jessica, Raman, Priya
• Format: Article
• Language: English
• Subjects: atherosclerosis; Cardiovascular Medicine; KKAy mice; metabolic syndrome; sex-specific differences; SMC differentiation; TSP-1
• ISSN: 2297-055X; 2297-055X
• DOI: 10.3389/fcvm.2022.1020006

Metabolic syndrome (MetS) amplifies the risks of atherosclerosis. Despite well-known sexual dimorphism in atherosclerosis, underlying mechanisms are poorly understood. Our previous findings highlight a proatherogenic protein, thrombospondin-1 (TSP-1), in hyperglycemia- or hyperleptinemia (mimicking obesity)-induced atherosclerosis. However, the role of TSP-1 in the development of atherosclerosis prompted by co-existing hyperglycemia and obesity, characteristic of MetS, is unknown. The goal of this study was to examine sex-specific differences in lesion progression in a model of combined MetS and atherosclerosis (KKAyApoE) and interrogate how these differences relate to TSP-1 expression. Male and female KKAy ApoE (with ectopic agouti gene expression) and age-matched non-agouti KKAy ApoE littermates were placed on a standard laboratory diet from 4 to 24 weeks age followed by blood and tissue harvests for biochemical, molecular, and aortic root morphometric studies. Metabolic profiling confirmed MetS phenotype of KKAy ApoE ; however, only male genotypes were glucose intolerant with elevated VLDL-cholesterol and VLDL-triglyceride levels. Aortic root morphometry demonstrated profound lipid-filled lesions, increased plaque area, and augmented inflammatory and SMC abundance in MetS vs non-MetS males. This increase in lesion burden was accompanied with elevated TSP-1 and attenuated LMOD-1 (SM contractile marker) and SRF (transcriptional activator of SM differentiation) expression in male MetS aortic vessels. In contrast, while lipid burden, plaque area, and TSP-1 expression increased in MetS and non-MetS female mice, there was no significant difference between these genotypes. Increased collagen content was noted in MetS and non-MetS genotypes, specific to female mice. Measurement of plasma testosterone revealed a link between the atherogenic phenotype and abnormally high or low testosterone levels. To interrogate whether TSP-1 plays a direct role in SMC de-differentiation in MetS, we generated KKAy mice with and without global TSP-1 deletion. Immunoblotting showed increased SM contractile markers in male KKAy TSP-1 aortic vessels vs male KKAy TSP-1 . In contrast, TSP-1 deletion had no effect on SM contractile marker expression in female genotypes. Together, the current study implicates a role of plasma testosterone in sex-specific differences in atherosclerosis and TSP-1 expression in MetS vs non-MetS mice. Our data suggest a sex-dependent differential role of TS