KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis
Open accessAbstract
Previous studies investigating the role of smooth muscle cells (SMCs) and macrophages in the pathogenesis of atherosclerosis have provided controversial results owing to the use of unreliable methods for clearly identifying each of these cell types. Here, using Myh11-CreER(T2) ROSA floxed STOP eYFP Apoe(-/-) mice to perform SMC lineage tracing, we find that traditional methods for detecting SMCs based on immunostaining for SMC markers fail to detect >80% of SMC-derived cells within advanced atherosclerotic lesions. These unidentified SMC-derived cells exhibit phenotypes of other cell lineages, including macrophages and mesenchymal stem cells (MSCs). SMC-specific conditional knockout of Krüppel-like factor 4 (Klf4) resulted in reduced numbers of SMC-derived MSC- and macrophage-like cells, a marked reduction in lesion size, and increases in multiple indices of plaque stability, including an increase in fibrous cap thickness as compared to wild-type controls. On the basis of in vivo KLF4 chromatin immunoprecipitation-sequencing (ChIP-seq) analyses and studies of cholesterol-treated cultured SMCs, we identified >800 KLF4 target genes, including many that regulate pro-inflammatory responses of SMCs. Our findings indicate that the contribution of SMCs to atherosclerotic plaques has been greatly underestimated, and that KLF4-dependent transitions in SMC phenotype are critical in lesion pathogenesis.
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Definition of cell-type based on functionality or 'specific' markers as a proxy for cell identification is problematic and has confounded studies on the true extent of the role of VSMCs in atherosclerosis.
“Hence, definition of cell-type based on functionality or 'specific' markers as a proxy for cell identification is problematic, and has confounded studies on the true extent of the role of VSMCs in atherosclerosis 11 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [11]
Lineage tracing studies have unambiguously demonstrated that VSMCs contribute substantially to plaque formation in murine models of atherosclerosis, generating 30-70% of all plaque cells.
“Lineage tracing studies have unambiguously demonstrated that VSMCs contribute substantially to plaque formation in murine models of atherosclerosis, generating 30-70% of all plaque cells 11,18-20,22,23 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [11]
Some plaque reporter-expressing cells were positive for Mac-3, Lgals3 and CD68, markers previously used to study macrophages in atherosclerosis.
“Instead, some plaque reporter-expressing cells were positive for Mac-3 20 , Lgals3 11 and CD68 17 - markers that have been previously used to study macrophages in atherosclerosis.”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [11]
VSMC-derived cells that express mesenchymal stem cell markers (in particular Sca1) have been identified in the healthy media and in plaques.
“VSMC-derived cells that express mesenchymal stem cell markers (in particular Sca1) have also been identified in the healthy media 43 and in plaques 11,43 , and may represent a plastic intermediate population that is readily responsive to inflammation and capable of generating contractile or phenotypically switched VSMCs 43 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [11]
Within plaques a large proportion of reporter-expressing VSMC-derived cells do not have detectable levels of the contractile smooth muscle cell marker αSMA.
“Within plaques a large proportion of reporter-expressing VSMC-derived cells do not have detectable levels of the contractile smooth muscle cell marker α SMA 11,20 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [11]
Potential VSMC progenitor populations have been identified in the media in the adult mouse, including VSMC-derived cells expressing Sca1 and other mesenchymal stem cell markers.
“Potential VSMC progenitor populations have also been identified in the media in the adult mouse, including VSMC-derived cells expressing Sca1 and other mesenchymal stem cell markers 11,43 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [11]
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Vascular Smooth Muscle Cell Plasticity and Autophagy in Dissecting Aortic Aneurysms
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Extracellular matrix proteomics identifies molecular signature of symptomatic carotid plaques
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Genetic Regulatory Mechanisms of Smooth Muscle Cells Map to Coronary Artery Disease Risk Loci
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Lineage tracing of cells involved in atherosclerosis
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Efficacy and limitations of senolysis in atherosclerosis
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- Authors
- Shankman, L. S., Gomez, D., Cherepanova, O. A., Salmon, M., Alencar, G. F., Haskins, R. M., Swiatlowska, P., Newman, A. A. C., Greene, E. S., Straub, A. C., Isakson, B., Randolph, G. J., & Owens, G. K.
- Affiliations
- University of Virginia (US)
- University of Gdańsk (PL)
- University of Pittsburgh (US)
- Washington University in St. Louis (US)
- Corresponding author
- Owens, Gary K
- ORCID
- Venue
- Nature Medicine
- Published
- 2015-05-18
- Volume
- 21
- Issue
- 6
- Pages
- 628-637
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4552085
- OpenAlex
- W3103761932
- Cited by
- 1,218
- References
- 63
- Citations by year
- 2026: 116 · 2025: 105 · 2024: 121 · 2023: 133 · 2022: 147 · 2021: 146 · 2020: 110 · 2019: 83 · 2018: 94 · 2017: 75 · 2016: 71 · 2015: 12 · 2012: 1
- FWCI
- 41.04
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-02-04)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL087867, R00HL112904, K99HL112904, R01HL088554, R01HL087867, R01HL057353, R37HL057353, R01HL098538, HL-112904, R01HL121008, T32HL007284)
- National Cancer Institute (T32CA009109, P30CA044579)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- KLF4, smooth muscle cells, atherosclerosis, atherosclerotic plaque, macrophage-like cells, mesenchymal stem cells, plaque stability, fibrous cap thickness, pro-inflammatory genes, ApoE-deficient mice
- MeSH terms
- Kruppel-Like Factor 4, Animals, Apolipoproteins E, Cell Differentiation, Humans, Macrophages, Promoter Regions, Genetic, Cell Lineage, Myocytes, Smooth Muscle, Atherosclerosis, Mice, Kruppel-Like Transcription Factors, Plaque, Atherosclerotic, Cell Tracking, Mesenchymal Stem Cells
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