Analysis of vascular cell senescence to identify interventions in atherosclerosis

National Institute On Aging

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Abstract

The development of age-related multi-factorial diseases such as atherosclerosis is associated with persistent systemic inflammation. However, the interplay between aging, inflammation, and VSMC senescence is not well understood. Senescent cells exhibit a senescence-associated secretory phenotype (SASP) that includes the production of many proinflammatory cytokines (e.g., IL-6, IL-8, and IL-1), as well as chemokines (e.g., CCL2), adhesion molecules (e.g., ICAM-1), and angiogenic factors (e.g., VEGF). Recently, we have identified and published interesting a few candidates that regulate cell senescence and aging (Herman et. al., Nucleic Acid Res, 2021; Anerillas et al., Nature Communications, 2022; Tsitsipatis et. al., Aging Cell, 2022; Rossi et al., Elife, 2023) and published a review on lncRNAs (Herman et al., Mol Cell, 2022) and the epigenetic regulation of cardiovascular disease (Herman et al., J Cardiovascular Aging, 2021), both representing areas that may control processes key to cellular senescence and aging. Recent findings from our group discovered DPP4 protein levels and enzymatic activity increased in senescent human VSMCs (hVSMCs) senescence. DPP4 inhibition reduced senescent cell burden and coagulation in atherosclerotic mice, suggesting that downstream factors affected by DPP4 activity may be promising therapeutic targets in vascular diseases (Herman et al., Journal of Clinical Investigation, 2023). We are particularly interested in using omics technology and tools to assess the presence and role of senescent cells in cardiovascular disease and aging (Mahoney…Herman, AJP Heart and Circ. Phys, 2023). To explore the heterogeneity of senescent vascular cells and identify potential druggable pathways to counter senescence, we utilized an atherosclerotic mouse model. In a subset of HFD (atherosclerotic) mice, some were left untreated, while others were treated with senolytic drug ABT-737 to selectively eliminate senescent cells. Aortas from ABT-737-treated mice exhibited increased collagen deposition and reduced arterial stiffness. Paired with pseudo-bulk RNA-sequencing analysis, we observed that HFD-induced extracellular matrix (ECM) remodeling genes were diminished by ABT-737, suggesting that ECM-platelet interactions may be influenced by senescence. Single-cell RNA-sequencing analysis from aortas identified distinct cell clusters for each expected cell type. Utilizing Gene Set Enrichment Analysis with the SenMayo and CellAge panels, we identified four cell clusters exhibiting increased senescent features that were mitigated by ABT-737. These included two VSMC clusters, fibroblasts, and T cells. Unbiased subclustering of potentially senescent clusters revealed a small population of cells enriched with HFD and reduced by ABT-737, confirming their senescent nature. In the most abundant cluster, Spp1 strongly represented the senescent VSMC subpopulation, enriched for TGFβ signaling, ECM remodeling, and coagulation cascade genes. Further, we validated these findings through spatial transcriptomics and single-molecule FISH of brachiocephalic arteries from atherosclerotic mice and atherosclerotic mice depleted of senescent cells. Our results reveal a functional transcriptomic signature for senescent vascular cells that holds potential for therapeutic targeting in age-related vascular diseases (Mazan-Mamczarz et al., Nature Aging 2025).