Sources of cells that contribute to atherosclerotic intimal calcification: an in vivo genetic fate mapping study
Open accessAbstract
AIMS: Vascular cartilaginous metaplasia and calcification are common in patients with atherosclerosis. However, sources of cells contributing to the development of this complication are currently unknown. In this study, we ascertained the origin of cells that give rise to cartilaginous and bony elements in atherosclerotic vessels. METHODS AND RESULTS: We utilized genetic fate mapping strategies to trace cells of smooth muscle (SM) origin via SM22α-Cre recombinase and Rosa26-LacZ Cre reporter alleles. In animals expressing both transgenes, co-existence within a single cell of β-galactosidase [marking cells originally derived from SM cells (SMCs)] with osteochondrogenic (Runx2/Cbfa1) or chondrocytic (Sox9, type II collagen) markers, along with simultaneous loss of SM lineage proteins, provides a strong evidence supporting reprogramming of SMCs towards osteochondrogenic or chondrocytic differentiation. Using this technique, we found that vascular SMCs accounted for ~80% of Runx2/Cbfa1-positive cells and almost all of type II collagen-positive cells (~98%) in atherosclerotic vessels of LDLr-/- and ApoE-/- mice. We also assessed contribution from bone marrow (BM)-derived cells via analysing vessels dissected from chimerical ApoE-/- mice transplanted with green fluorescence protein-expressing BM. Marrow-derived cells were found to account for ~20% of Runx2/Cbfa1-positive cells in calcified atherosclerotic vessels of ApoE-/- mice. CONCLUSION: Our results are the first to definitively identify cell sources attributable to atherosclerotic intimal calcification. SMCs were found to be a major contributor that reprogrammed its lineage towards osteochondrogenesis. Marrow-derived cells from the circulation also contributed significantly to the early osteochondrogenic differentiation in atherosclerotic vessels.
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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 [138]
Most of the osteochondrogenic precursors (Runx2/Cbfa1+ cells) and chondrocyte-like (type II collagen+) cells of murine plaques are VSMC-derived.
“established that most of the osteochondreogenic precursors (Runx2/Cbfa1+ cells) and chondrocyte-like (type II collagen+) cells of murine plaques are”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [138]
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- Authors
- Naik, V., Leaf, E. M., Hu, J. H., Yang, H.-Y., Nguyen, N. B., Giachelli, C. M., & Speer, M. Y.
- Affiliations
- University of Washington (US)
- Corresponding author
- Speer, Mei Y.
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-03-21
- Volume
- 94
- Issue
- 3
- Pages
- 545-554
- ISSN
- 0008-6363 (ISSN-L)
- 1755-3245
- PMC
- PMC3353803
- OpenAlex
- W2141499934
- Cited by
- 149
- References
- 29
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 9 · 2023: 12 · 2022: 14 · 2021: 17 · 2020: 8 · 2019: 10 · 2018: 8 · 2017: 10 · 2016: 7 · 2015: 11 · 2014: 5 · 2013: 15 · 2012: 9
- FWCI
- 5.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cardiovascular Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL080597, R01HL062329, R01HL081785, R01HL62329)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK075665, P30DK017047)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cerebrovascular and Carotid Artery Diseases
- Keywords
- vascular smooth muscle cells, osteochondrogenic differentiation, chondrogenic differentiation, cell of origin, bone marrow-derived cells, genetic fate mapping, Runx2/Cbfa1, type II collagen, chondrocytes, ApoE-deficient mice, Ldlr-deficient mice, cellular reprogramming
- MeSH terms
- Animals, beta-Galactosidase, Bone Marrow Cells, Calcification, Physiologic, Cell Differentiation, Cells, Cultured, Macrophages, Mice, Knockout, Cell Lineage, Myocytes, Smooth Muscle, Atherosclerosis, Mice
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