{"doi":"10.3389/fcvm.2022.1020006","title":"Sex-specific differences in atherosclerosis, thrombospondin-1, and smooth muscle cell differentiation in metabolic syndrome versus non-metabolic syndrome mice","abstract":"Introduction 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. Methods 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. Results 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. Conclusion 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 TSP-1 on SMC de-differentiation in MetS. Collectively, these findings underscore a fundamental link between TSP-1 and VSMC phenotypic transformation in MetS.","journal":"Frontiers in Cardiovascular Medicine","year":2022,"id":267382,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":928438,"name":"Saugat Khanal","orcid":null,"position":1,"is_corresponding":false},{"id":708294,"name":"Neha Bhavnani","orcid":null,"position":2,"is_corresponding":false},{"id":928439,"name":"Amy Mathias","orcid":null,"position":3,"is_corresponding":false},{"id":928440,"name":"Jason Lallo","orcid":null,"position":4,"is_corresponding":false},{"id":928441,"name":"Ariana Kiriakou","orcid":null,"position":5,"is_corresponding":false},{"id":291733,"name":"Jessica M. Ferrell","orcid":"0000-0003-3691-3330","position":6,"is_corresponding":false},{"id":927993,"name":"Priya Raman","orcid":"0000-0002-7519-2524","position":7,"is_corresponding":false},{"id":927992,"name":"Shreya Gupta","orcid":"0000-0002-4069-9317","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T00:27:02.050512Z","pmid":"36505365","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}