ArticleArteriosclerosis, thrombosis, and vascular biology2021
Cholesterol-Induced Phenotypic Modulation of Smooth Muscle Cells to Macrophage/Fibroblast-like Cells Is Driven by an Unfolded Protein Response.
Article in Arteriosclerosis, thrombosis, and vascular biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers.
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Who cites it
80 citing papers in PubMed, 108 citations in OpenAlex.
- 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
- Energetic Decoding of VSMC Plasticity: Metabolic Reprogramming and Phenotypic Switching.Cardiovascular drugs and therapy · 2026Review
- Atherosclerotic Cell Fates: A Single-Cell View of ER Stress.Journal of cardiovascular development and disease · 2026Review
- Leiomodin 1 deficiency promotes lipid accumulation and redirects gene regulatory programs in smooth muscle cells exposed to oxidized LDL.Research square · 2026Article
- Single-cell analysis of the progeria arterial wall reveals progerin-induced progressive, cell type-specific dysfunction and somatic mutation accumulation.Genome medicine · 2026Article
- PERK Is Dispensable for Smooth Muscle Cell Phenotype Switching in Atherosclerosis.Arteriosclerosis, thrombosis, and vascular biology · 2026Article
- Atherosclerosis Profiling Reveals BHLHE40 as a Candidate Modulator of VSMC.Circulation research · 2026Article
- ADAMTS7 promotes smooth muscle foam cell expansion in atherosclerosis.The Journal of clinical investigation · 2026Article
- HDL Regulates TGFβ-Receptor Lipid Raft Partitioning, Restoring Contractile Features of Cholesterol-Loaded Vascular Smooth Muscle Cells.JACC. Basic to translational science · 2026Article
- ARF6 controls VSMC phenotypic switching upon lipid stimulation to promote inflammatory signaling contributing to the progression of atherosclerosis.The Journal of biological chemistry · 2026Article
- Article
- Activating transcription factors: Orchestrators of macrophage biology in pathological settings (Review).International journal of molecular medicine · 2026Review
- Advances regarding the mechanism of endoplasmic reticulum stress in diabetic kidney disease and pharmacological interventions (Review).Molecular medicine reports · 2026Review
- MAPK14 converges on key transcriptional machinery to promote vascular smooth muscle cell degeneration in abdominal aortic aneurysm.Signal transduction and targeted therapy · 2026Article
- VSMCs and the immune microenvironment: a multidimensional regulatory network driving vascular injury and repair.Frontiers in immunology · 2026Review
- Immune checkpoint inhibitor-driven smooth muscle cell phenotypic modulation: a potential contributor to atherosclerotic risk associated with these therapies.Frontiers in cardiovascular medicine · 2026Article
- Bidirectional crosstalk between ER stress and lipid metabolism: From proteostasis to tumor adaptation.Cell death discovery · 2025Review
- Review
- Mapping atherogenesis mechanisms in smooth muscle cells by targeting genes linked to coronary artery disease.iScience · 2025Article
- Macrophage-like smooth muscle cells in atherosclerosis.Molecular biology reports · 2025Review
20 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
objectiveVascular smooth muscle cells (SMCs) dedifferentiate and initiate expression of macrophage markers with cholesterol exposure. This phenotypic switching is dependent on the transcription factor Klf4 (Krüppel-like factor 4). We investigated the molecular pathway by which cholesterol induces SMC phenotypic switching. Approach and Results: With exposure to free cholesterol, SMCs decrease expression of contractile markers, activate Klf4, and upregulate a subset of macrophage and fibroblast markers characteristic of modulated SMCs that appear with atherosclerotic plaque formation. These phenotypic changes are associated with activation of all 3 pathways of the endoplasmic reticulum unfolded protein response (UPR), Perk (protein kinase RNA-like endoplasmic reticulum kinase), Ire (inositol-requiring enzyme) 1α, and Atf (activating transcription factor) 6. Blocking the movement of cholesterol from the plasma membrane to the endoplasmic reticulum prevents free cholesterol-induced UPR, Klf4 activation, and upregulation of the majority of macrophage and fibroblast markers. Cholesterol-induced phenotypic switching is also prevented by global UPR inhibition or specific inhibition of Perk signaling. Exposure to chemical UPR inducers, tunicamycin and thapsigargin, is sufficient to induce these same phenotypic transitions. Finally, analysis of published single-cell RNA sequencing data during atherosclerotic plaque formation in hyperlipidemic mice provides preliminary in vivo evidence of a role of UPR activation in modulated SMCs.
conclusionsOur data demonstrate that UPR is necessary and sufficient to drive phenotypic switching of SMCs to cells that resemble modulated SMCs found in atherosclerotic plaques. Preventing a UPR in hyperlipidemic mice diminishes atherosclerotic burden, and our data suggest that preventing SMC transition to dedifferentiated cells expressing macrophage and fibroblast markers contributes to this decreased plaque burden.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.