ArticleCardiovascular research2025
Premature cell senescence promotes vascular smooth muscle cell phenotypic modulation and resistance to re-differentiation.
Article in Cardiovascular research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Salvianolic Acid a Disrupts the HSP90α-AKT-PERK Ternary Complex to Alleviate Atherosclerosis by Activating Endoplasmic Reticulum Stress of Senescent Vascular Smooth Muscle Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The senescence-stiffening loop: Extracellular matrix remodeling, hypoperfusion, and mitochondrial dysfunction drive tissue aging.Cell metabolism · 2026Review
- USP5 Stabilizes TGFBR1 to Drive Vascular Smooth Muscle Cell Senescence and Atherosclerosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Vascular Smooth Muscle Cell Plasticity in Atherosclerosis: Mechanisms, Recent Advances, and Therapeutic Implications.Reviews in cardiovascular medicine · 2026Review
- Integrin-Linked Kinase Plays an Active Role in the Regulation of Endothelial Senescence.Cells · 2026Article
- PCSK9 in vascular smooth muscle cells: biology, pathology, and inhibition to fight atherosclerosis.Atherosclerosis plus · 2026Review
- Genetic factors contributing to atherosclerosis.Current opinion in cardiology · 2026Review
- Integration of Multi-Omics and Machine Learning Identifies TGFB1 and SERPINE1 as Biomarkers of Vascular Smooth Muscle Cell Senescence in Intracranial Aneurysms.Translational stroke research · 2026Article
- A Comprehensive Review of Epigenetic Regulation of Vascular Smooth Muscle Cells During Development and Disease.Biomolecules · 2026Review
- Review
- Endothelial-to-mesenchymal transition in atherosclerosis: mechanisms, therapeutic targets, and future perspectives.Frontiers in cell and developmental biology · 2026Review
- The role of interferon regulatory factors in atherosclerosis: from cell type-specific mechanisms to therapeutic strategies.Frontiers in cell and developmental biology · 2026Review
- Low Dose GLP-1 Therapy Attenuates Pathological Cardiac and Hepatic Remodelling in HFpEF Independent of Weight Loss.bioRxiv : the preprint server for biology · 2025Article
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Authors and funding
13 authors.
Funding
Abstract
aimsHuman atherosclerotic plaque cells display DNA damage that if left unrepaired can promote premature cell senescence. Vascular smooth muscle cells (VSMCs) predisposed to senescence promote atherogenesis and features of unstable plaques and increase neointima formation after injury. However, how premature VSMC senescence promotes vascular disease and its effects on VSMC phenotype are unknown. METHODS AND
resultsBulk RNA-seq of primary human VSMCs identified 126 significantly up- or down-regulated genes after both DNA damage-induced (D + R) or replicative senescence (RS). Up-regulated genes included senescence markers CDKN2A (p16) and ICAM1 and genes expressed by phenotypically modulated de-differentiated/'fibromyocytic' VSMCs [osteoprotegerin (TNFRSF11B), fibromodulin (FMOD)] as well as transmembrane protein 178B (TMEM178B) and secreted frizzle-related protein 4 (SFRP4). Mouse VSMCs also up-regulated genes associated with de-differentiated VSMC phenotype, Tmem178b and Sfrp4 after D + R. Single-cell RNA-sequencing of lineage-traced VSMCs in mouse plaques or human plaques showed that VSMCs expressing Cdkn2a had lower contractile marker expression and higher expression of de-differentiated VSMC markers. Mice expressing a VSMC-restricted mutant telomere protein (TRF2T188A) that induces premature senescence showed increased atherosclerosis, expression of multiple de-differentiation genes in plaques and after injury, and differential regulation of pathways associated with extracellular matrix organization, inflammation and Transforming Growth Factor-β (Tgfb). Trf2T188A VSMCs were more resistant to re-differentiation and had dysregulated Tgfb signalling at multiple levels with down-regulated ligands, receptors, and coactivators and up-regulated co-repressor expression. Trf2T188A VSMCs also showed cytosolic DNA and activation of the STING-TBK1-IRF3 pathway that suppressed Tgfb signalling. Silencing IRF3 restored expression of Tgfb pathway components and VSMC contractile markers after TGFb administration.
conclusionDNA damage and senescence induce genes associated with de-differentiated/fibromyocytic VSMCs, and persistence of these cells in vivo. Failure of senescent VSMCs to re-express contractile markers during re-differentiation suggests that VSMC senescence may promote atherosclerosis and neointima formation in part by inhibiting their re-differentiation.
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