Romay Milagros C, Ma Feiyang, Mompeón Ana, Silvestro Michele, Hernandez Gloria E, Salvador Jocelynda, Wang Andrew L, Vandestienne Marie, Bardin Nathalie, Blot-Chabaud Marcel, Leroyer Aurelie S, Ait-Oufella Hafid, Ramkhelawon Bhama, Iruela-Arispe M Luisa
Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Division of Vascular and Endovascular Surgery, Department of Surgery, New York University Langone Health, New York, NY, USA.
Nat Cardiovasc Res. 2025 Aug 21. doi: 10.1038/s44161-025-00692-4.
Pathology in large vessels frequently develops at specific locations, implying that local stressors and spatially restricted gene expression are likely contributors to disease susceptibility. Here we perform single-cell transcriptomics in the carotids, the aortic arch and the thoracic and abdominal aorta to identify site- and sex-specific differences that could inform about vulnerability. Our findings revealed (1) regionally defined transcriptional profiles, (2) signatures associated with embryonic origins and (3) differential contributions of sex-specific effectors. Furthermore, cross-referencing regional-specific signatures with available genome-wide association study and expression quantitative trait loci databases identified 339 disease candidates associated with aorta distensibility, stiffness index and blood pressure. CPNE8 and SORBS2 were further evaluated and highlighted as strong causal candidates. Sex differences were predominantly observed in the thoracic and abdominal aorta. MCAM (CD146), a transcript with sex-skewed expression and lower in male mice and men, had significantly reduced expression in human aortic aneurysms. The findings reveal underlying diversity within vascular smooth muscle cell populations relevant to understanding site-specific and sex-specific variation of vascular pathologies.
大血管病变常发生于特定部位，这表明局部应激源和空间受限的基因表达可能是疾病易感性的促成因素。在此，我们对颈动脉、主动脉弓以及胸主动脉和腹主动脉进行单细胞转录组学分析，以确定可能与易损性相关的部位和性别特异性差异。我们的研究结果揭示了：（1）区域特异性转录谱；（2）与胚胎起源相关的特征；（3）性别特异性效应器的不同作用。此外，将区域特异性特征与现有的全基因组关联研究和表达数量性状位点数据库进行交叉比对，确定了339个与主动脉扩张性、僵硬度指数和血压相关的疾病候选基因。对CPNE8和SORBS2进行了进一步评估，并将其作为强有力的因果候选基因加以强调。性别差异主要在胸主动脉和腹主动脉中观察到。MCAM（CD146）是一种在雄性小鼠和男性中表达呈性别偏态且较低的转录本，在人类主动脉瘤中表达显著降低。这些发现揭示了血管平滑肌细胞群体中的潜在多样性，这与理解血管病变的部位特异性和性别特异性差异相关。
