Single-cell and spatial transcriptomics map senescent vascular cells in arterial remodeling during atherosclerosis in mice

  • Nat Aging. 2025 Aug;5(8):1528-1547. doi: 10.1038/s43587-025-00889-z.
Krystyna Mazan-Mamczarz  #  1 ,  Dimitrios Tsitsipatis  #  2 ,  Bennett G Childs  3 ,  Angelica E Carr  1 ,  Carla Rocha Dos Santos  2 ,  Carlos Anerillas  1 ,  Brigette Romero  4 ,  Jordan M Gregg  1 ,  Charnae' Henry-Smith  1 ,  Ada N Okereke  1 ,  Marc Michel  1 ,  Rachel Munk  1 ,  Jennifer L Martindale  1 ,  Yulan Piao  1 ,  Jinshui Fan  1 ,  Maria O Hernandez  5 ,  Noemi Kedei  5 ,  Michael L Viacheslavov  6 ,  Madeline M F Wong  5 ,  Olga V Fedorova  2 ,  Mona Batish  4 ,  Supriyo De  1 ,  Darren J Baker  3 ,  Myriam Gorospe  7 ,  Allison B Herman  8
Affiliations
  • 1. Laboratory of Genetics and Genomics, National Institute on Aging (NIA) Intramural Research Program (IRP), National Institutes of Health (NIH), Baltimore, MD, USA.
  • 2. Laboratory of Cardiovascular Science, NIA IRP, NIH, Baltimore, MD, USA.
  • 3. Department of Biochemistry and Molecular Biology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
  • 4. Department of Medical and Molecular Sciences, University of Delaware, Newark, DE, USA.
  • 5. Center for Cancer Research, National Cancer Institute IRP, NIH, Bethesda, MD, USA.
  • 6. Seqmatic LLC, Fremont, CA, USA.
  • 7. Laboratory of Genetics and Genomics, National Institute on Aging (NIA) Intramural Research Program (IRP), National Institutes of Health (NIH), Baltimore, MD, USA. [email protected].
  • 8. Laboratory of Cardiovascular Science, NIA IRP, NIH, Baltimore, MD, USA. [email protected].
  • # Contributed equally.
PMID: 40660002 DOI: 10.1038/s43587-025-00889-z
Abstract

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.