Integrin beta3 regulates clonality and fate of smooth muscle-derived atherosclerotic plaque cells
Open accessAbstract
Smooth muscle cells (SMCs) play a key role in atherogenesis. However, mechanisms regulating expansion and fate of pre-existing SMCs in atherosclerotic plaques remain poorly defined. Here we show that multiple SMC progenitors mix to form the aorta during development. In contrast, during atherogenesis, a single SMC gives rise to the smooth muscle-derived cells that initially coat the cap of atherosclerotic plaques. Subsequently, highly proliferative cap cells invade the plaque core, comprising the majority of plaque cells. Reduction of integrin β3 (Itgb3) levels in SMCs induces toll-like receptor 4 expression and thereby enhances Cd36 levels and cholesterol-induced transdifferentiation to a macrophage-like phenotype. Global Itgb3 deletion or transplantation of Itgb3 (−/−) bone marrow results in recruitment of multiple pre-existing SMCs into plaques. Conditioned medium from Itgb3-silenced macrophages enhances SMC proliferation and migration. Together, our results suggest SMC contribution to atherogenesis is regulated by integrin β3-mediated pathways in both SMCs and bone marrow-derived cells.
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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 [23]
Observations of plaques at different timepoints suggest that, in mice, VSMCs first generate the cap followed by adoption of switched phenotypes in the lesion core.
“Observations of plaques at different timepoints suggest that, in mice, VSMCs first generate the cap followed by adoption of switched phenotypes in the lesion core 23 , but”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [23]
Conditioned media from integrin β3-deficient macrophages is more mitogenic to VSMCs than conditioned media from wild-type macrophages.
“For example, bone-marrow transplantation from integrin β 3-deficient mice into ApoE null mice results in polyclonal plaque VSMCs and VSMC-derived cells 23 , whilst conditioned media from integrin β 3-deficient macrophages is more mitogenic to VSMCs than conditioned media from wild-type macrophages 23 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [23]
Bone-marrow transplantation from integrin β3-deficient mice into ApoE null mice results in polyclonal plaque VSMCs and VSMC-derived cells.
“For example, bone-marrow transplantation from integrin β 3-deficient mice into ApoE null mice results in polyclonal plaque VSMCs and VSMC-derived cells 23 , whilst conditioned media from integrin β 3-deficient macrophages is more mitogenic to VSMCs than conditioned media from wild-type macrophages 23 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [23]
In mice, fibrous cap VSMCs are derived from medial VSMCs that migrated and proliferated in response to cytokines and growth factors such as PDGF from macrophages and activated ECs.
“In mice, the fibrous cap VSMCs are derived from medial VSMCs 22,138 that have undergone migration and proliferation in response to cytokines and growth factors, such as PDGF, derived from macrophages and activated ECs 23,129,139 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [23]
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References 49 · Cited by 207
- Authors
- Misra, A., Feng, Z., Chandran, R. R., Kabir, I., Rotllan, N., Aryal, B., Sheikh, A. Q., Ding, L., Qin, L., Fernández-Hernando, C., Tellides, G., & Greif, D. M.
- Affiliations
- Yale University (US)
- Corresponding author
- Greif, Daniel M.
- ORCID
- Venue
- Nature Communications
- Published
- 2018-05-25
- Volume
- 9
- Issue
- 1
- Pages
- 2073-2073
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5970166
- OpenAlex
- W2803608485
- Cited by
- 207
- References
- 49
- Citations by year
- 2026: 23 · 2025: 23 · 2024: 28 · 2023: 30 · 2022: 30 · 2021: 36 · 2020: 17 · 2019: 17 · 2018: 3
- FWCI
- 7.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- American Heart Association (14GRNT19990019)
- Yale University
- National Heart, Lung, and Blood Institute (R01HL133016, R01HL125815)
- National Institute of Neurological Disorders and Stroke (R21NS088854)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- CD61, smooth muscle cells, atherosclerosis, atherosclerotic plaque, CD36, cholesterol, TLR4, bone marrow-derived cells, aortic development
- MeSH terms
- Mice, Knockout, ApoE, Animals, Aorta, Cell Movement, Cells, Cultured, Cholesterol, Disease Models, Animal, Female, Humans, Macrophages, Male, Mice, Inbred C57BL, Muscle, Smooth, Vascular, Bone Marrow Transplantation, Myocytes, Smooth Muscle, Integrin beta3, Cell Proliferation, Atherosclerosis, Mice, Cell Transdifferentiation, Plaque, Atherosclerotic
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