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REGION-SPECIFIC GENE EXPRESSION AND SEX INFORM ABOUT DISEASE SUSCEPTIBILITY IN THE AORTA - MCAM Knockdown

ABSTRACT: Pathology in large vessels frequently develops at specific locations, implying that local stressors and spatially restricted gene expression are likely contributors to disease susceptibility. To identify site- and sex-specific differences that could inform about vulnerability, we performed single-cell transcriptomics in the carotids, aortic arch, thoracic, and abdominal aorta. Our findings revealed: (1) regionally defined transcriptional profiles, (2) signatures associated with embryonic origins, and (3) differential contributions of sex-specific effectors. Sex differences were predominantly observed in the thoracic and abdominal aorta. MCAM/CD146, a transcript with sex-skewed expression in vSMC of the abdominal aorta showed a 2.5-fold lower expression in males when compared to females. siRNA knockdown was performed to identify downstream targets of MCAM in vascular smooth muscle cells and to assess if sex affected number and biological function of genes modulated by changes in MCAM expression. MCAM was found to be further downregulated in vSMC associated with aortic aneurysms in humans. The findings reveal underlying diversity within vSMC populations with relevance to understanding site-specific and sex-specific variation of vascular pathologies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292995 | GEO | 2025/06/30

REPOSITORIES: GEO

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Project description:Pathologies of large vessels, such as atherosclerosis and aneurysms tend to develop at specific sites in the vascular tree. The consistency with which these events emerge suggests that a combination of unique local stressors, particularly physical forces and disturbances in gene expression profiles underlies disease etiology. We sought to investigate whether transcriptional diversity in specific segments of the aorta could be used to identify emergence of site-restricted vascular disease. Transcriptional profiling was performed using single cell RNA-seq in the carotids, aortic arch, thoracic and abdominal aorta across both sexes. Analyses of the data identified sex-invariant region-specific differences that were further validated by immunocytochemistry. Analysis of vascular smooth muscle cell transcriptomics from distinct regions of the aorta and carotids showed a high degree of similarity, but also uncovered skewed expression of a small percentage of transcripts (7.2%) towards particular vascular segments (carotid, aortic arch, thoracic and abdominal aorta). In silico cross-reference of genes known to be associated with vascular disease with the unique transcriptional signatures validated our proposed hypothesis. Specifically, we found correlations between localized-diseased causing GWAS candidate genes and region-enriched signatures. Pair-wise comparison between anatomic regions across sexes identified regional sex-specific gene signatures highlighting prominent regional-sex dependent differences were observed in vSMCs of the thoracic and abdominal aorta, consistent with sex-specific burden of aneurysm in these regions. Of these regional sex-enriched candidates’, Mcam/CD146, showed ventral thoraco-abdominal distribution, enriched expression in females and it was significantly reduced in the AngII / hypercholesterolemic model of aortic aneurysm. Furthermore, induction of aneurysms in mice lacking Mcam/CD146 resulted in larger lesions and accelerated death due to dissection.

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REGION-SPECIFIC GENE EXPRESSION AND SEX INFORM ABOUT DISEASE SUSCEPTIBILITY IN THE AORTA - MCAM Knockdown

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