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

Krystyna Mazan-Mamczarz ¹, Dimitrios Tsitsipatis ², Bennett G Childs ³

⁰Laboratory of Genetics and Genomics, National Institute on Aging (NIA) Intramural Research Program (IRP), National Institutes of Health (NIH), Baltimore, MD, USA.

Nature Aging +

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July 14, 2025

View abstract on PubMed

Summary

Cellular senescence in vascular cells contributes to cardiovascular diseases. This study identified a vascular-specific senescence signature in atherosclerosis, offering potential targets for treatment.

Area Of Science

Cardiovascular Biology
Cellular Senescence
Atherosclerosis Research

Background

Cellular senescence in vascular cells is increasingly linked to cardiovascular disease development.
Understanding the diversity of senescent vascular cells in atherosclerosis is crucial for targeted therapies.

Purpose Of The Study

To systematically investigate the heterogeneity of senescent vascular cells during atherosclerosis.
To identify a specific transcriptomic signature of senescence in vascular cells associated with atherosclerosis.
To explore the therapeutic potential of targeting senescent cells in vascular diseases.

Main Methods

Induction of atherosclerosis in senescence reporter mice using a high-fat diet and PCSK9 overexpression.
Single-cell RNA sequencing of whole aortas to analyze senescent cell populations.
Treatment with the senolytic agent ABT-737 to assess the impact on senescent cells.
Validation using spatial transcriptomics in a second atherosclerosis model and in vitro human VSMC senescence models.

Main Results

Identification of four distinct clusters of senescent vascular smooth muscle cells (VSMCs), fibroblasts, and T cells.
Senescent cell populations were significantly reduced following treatment with the senolytic agent ABT-737.
Development of a global senescence signature for atherosclerosis, including Spp1, Ctsb, and Tnfrsf11b mRNAs.
Validation of the senescence signature in independent mouse models and human cell cultures.

Conclusions

Atherosclerosis involves a heterogeneous population of senescent vascular cells.
A specific vascular transcriptomic signature of senescence in atherosclerosis has been identified.
This signature holds potential for tracking and developing novel treatments for age-related vascular diseases.