Abstract 4360036: Estrogen Deficiency by Ovariectomy Triggers Phenotypic Switching in Female Aortic Smooth Muscle Cells in Atherosclerosis

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Background: The postmenopausal state increases atherosclerosis in women, yet the molecular and cellular mechanisms remain largely elusive. Smooth muscle cells (SMC) and their phenotypic modulation play a crucial role in atherosclerosis. How estrogen depletion alters SMC phenotype during atherosclerosis remains to be determined. Research Questions: We aimed to evaluate SMC characteristics and phenotypic modulation under estrogen influence in atherosclerosis. Methods: Ten Ldlr -knockout female mice (5 receiving ovariectomy, 5 receiving sham surgery at 12-week-old) were fed a Western diet to promote atherosclerosis. At 26-week-old, ascending aortae were isolated for single cell preparation and RNA sequencing. Analyses included cluster analysis, differentially expressed gene (DEG) analysis, proportion analysis, pathway enrichment analysis (PEA), and transcription factor analysis using Seurat v4.4. Results: Cluster analysis identified 15 distinct clusters, including 3 SMC clusters. DEG analysis of these SMC clusters revealed that SMC1 predominantly expressed contractile protein markers. SMC2 showed high expression of inflammatory markers proliferation markers, and reduced contractile marker expression. SMC3 exhibited generally low expression across all genes, particularly contractile proteins. Analysis of SMC characteristics under estrogen influence showed that the ovariectomy group had higher proportions of SMC1 and SMC2, while the sham group showed higher SMC3 proportions. DEG analysis revealed that SMCs in the ovariectomy group upregulated tissue fibrosis and inflammatory markers, and downregulated contractile markers. Transcription factor analysis indicated that SMCs in the ovariectomy group highly expressed transcription factors associated with inflammation, fibrosis, and developmental pathway reactivation, suggesting an intense inflammatory state with phenotypic changes. In contrast, SMCs in the sham group expressed transcription factors involved in cellular homeostasis and tissue plasticity, indicating a more stable state.PEA demonstrated that ovariectomized SMCs increased expression of genes involved in stress response and tissue remodeling, and reduced expression in contractile function, protein synthesis, and metabolic pathways. Conclusions: Estrogen deficiency by ovariectomy promotes SMC phenotypic switching in atherosclerosis towards a pro-inflammatory state with reduced contractile function, while estrogen maintains SMC homeostasis and stability.

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