ArticleJCI insight2025
Inhibition of vascular smooth muscle cell PERK/ATF4 ER stress signaling protects against abdominal aortic aneurysms.
Article in JCI insight, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- MTR4 deficiency attenuates abdominal aortic aneurysm progression through suppressing VSMC senescence via the MTR4-RAP1a axis.iScience · 2026Article
- Gut Dysbiosis, Sex, and Vascular Smooth Muscle Cells in Abdominal Aortic Aneurysms.Current atherosclerosis reports · 2026Review
- Review
- Endothelial ATF4 attenuates hypertensive vascular damage via preserving mitochondrial redox homeostasis.Molecular and cellular biochemistry · 2026Article
- Identification and Validation of Plasma Protein Biomarkers for Abdominal Aortic Aneurysm Using Integrated Proteomics.International journal of molecular sciences · 2026Article
- Tenascin C promotes the formation of abdominal aortic aneurysm by regulating the homeostasis of vascular smooth muscle cells.Biology direct · 2026Article
- Sex-specific prediction models for aortic aneurysm integrating traditional clinical risk factors and proteomic profiles: a large-scale prospective study from the UK Biobank.Biology of sex differences · 2026Article
- Role of Activating Transcription Factor 4 in Metabolic, Neurologic, and Ocular Diseases.Cells · 2026Review
- Oxidative Stress-Induced DNA Damage Response Pathways in Aortic Disease: Implications for Inflammation and Vascular Degeneration.International journal of molecular sciences · 2026Review
- VSMCs and the immune microenvironment: a multidimensional regulatory network driving vascular injury and repair.Frontiers in immunology · 2026Review
- Role of Programmed Cell Death in the Pathogenesis of Kawasaki Disease: Mechanisms and Therapeutic Implications.Mediators of inflammation · 2026Review
- NEXN regulates vascular smooth muscle cell phenotypic switching and neointimal hyperplasia.JCI insight · 2025Article
- Plasma Exosomal-Derived SERPINA1 and GNAI2 Downregulation as Potential Diagnostic Biomarkers of Kawasaki Disease with Coronary Artery Aneurysms.International journal of molecular sciences · 2025Article
- Therapeutic Targeting of Signaling Pathways in Abdominal Aortic Aneurysm: From Pathogenesis to Precision Medicine.Drug design, development and therapy · 2025Review
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
Abdominal aortic aneurysms (AAA) are a life-threatening cardiovascular disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by vascular smooth muscle cell (VSMC) dysfunction and apoptosis, for which the mechanisms regulating loss of VSMCs within the aortic wall remain poorly defined. Using single-cell RNA-Seq of human AAA tissues, we identified increased activation of the endoplasmic reticulum stress response pathway, PERK/eIF2α/ATF4, in aortic VSMCs resulting in upregulation of an apoptotic cellular response. Mechanistically, we reported that aberrant TNF-α activity within the aortic wall induces VSMC ATF4 activation through the PERK endoplasmic reticulum stress response, resulting in progressive apoptosis. In vivo targeted inhibition of the PERK pathway, with VSMC-specific genetic depletion (Eif2ak3fl/fl Myh11-CreERT2) or pharmacological inhibition in the elastase and angiotensin II-induced AAA model preserved VSMC function, decreased elastin fragmentation, attenuated VSMC apoptosis, and markedly reduced AAA expansion. Together, our findings suggest that cell-specific pharmacologic therapy targeting the PERK/eIF2α/ATF4 pathway in VSMCs may be an effective intervention to prevent AAA expansion.
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