Mazan-Mamczarz Krystyna, Tsitsipatis Dimitrios, Childs Bennett G, Carr Angelica E, Dos Santos Carla Rocha, Anerillas Carlos, Romero Brigette, Gregg Jordan M, Henry-Smith Charnae', Okereke Ada N, Michel Marc, Munk Rachel, Martindale Jennifer L, Piao Yulan, Fan Jinshui, Hernandez Maria O, Kedei Noemi, Viacheslavov Michael L, Wong Madeline M F, Fedorova Olga V, Batish Mona, De Supriyo, Baker Darren J, Gorospe Myriam, Herman Allison B
Laboratory of Genetics and Genomics, National Institute on Aging (NIA) Intramural Research Program (IRP), National Institutes of Health (NIH), Baltimore, MD, USA.
Laboratory of Cardiovascular Science, NIA IRP, NIH, Baltimore, MD, USA.
Nat Aging. 2025 Jul 14. doi: 10.1038/s43587-025-00889-z.
Growing evidence suggests that the induction of cellular senescence in vascular cells is causally linked to the etiology of cardiovascular diseases. To investigate systematically the heterogeneity of senescent vascular cells in atherosclerosis, we used a high-fat diet and PCSK9 overexpression to induce atherosclerosis in a senescence reporter mouse model (p16-tdTomato) and performed single-cell RNA sequencing on whole aortas. Using the SenMayo and CellAge gene sets, we identified four clusters of vascular smooth muscle cells (VSMCs), fibroblasts and T cells enriched in features of senescence, which were reduced upon treatment with the senolytic agent ABT-737. We then derived a global senescence signature of atherosclerosis including Spp1, Ctsb and Tnfrsf11b mRNAs. We validated the enrichment of these mRNAs in senescence by using spatial transcriptomics in a second mouse model of atherosclerosis and senolysis (Ldlr; p16-3MR), as well as by analyzing in vitro models of human VSMC senescence. Our results uncover a vascular-specific transcriptomic signature of senescence that may be exploited for tracking and treating age-related vascular diseases.
越来越多的证据表明，血管细胞中细胞衰老的诱导与心血管疾病的病因存在因果关系。为了系统地研究动脉粥样硬化中衰老血管细胞的异质性，我们使用高脂饮食和PCSK9过表达在衰老报告小鼠模型（p16-tdTomato）中诱导动脉粥样硬化，并对整个主动脉进行单细胞RNA测序。使用SenMayo和CellAge基因集，我们鉴定出四组富含衰老特征的血管平滑肌细胞（VSMC）、成纤维细胞和T细胞，在用衰老细胞溶解剂ABT-737处理后这些细胞减少。然后，我们得出了包括Spp1、Ctsb和Tnfrsf11b mRNA在内的动脉粥样硬化的整体衰老特征。我们通过在第二个动脉粥样硬化和衰老细胞溶解小鼠模型（Ldlr；p16-3MR）中使用空间转录组学，以及通过分析人类VSMC衰老的体外模型，验证了这些mRNA在衰老中的富集情况。我们的结果揭示了一种血管特异性的衰老转录组特征，可用于追踪和治疗与年龄相关的血管疾病。
