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Paracrine Osteogenic Signals via Bone Morphogenetic Protein-2 Accelerate the Atherosclerotic Intimal Calcification In Vivo
Open accessAbstract
Objective— Vascular calcification is an important risk factor for cardiovascular diseases. Here, we investigated a role of dedifferentiated vascular smooth muscle cells (VSMCs) in the atherosclerotic intimal calcification. Methods and Results— We prepared human cultured VSMCs in either redifferentiatiated or dedifferentiated state and analyzed the gene expressions of bone-calcification regulatory factors. Expression of bone morphogenetic protein-2 (BMP-2), a potent initiator for osteoblast differentiation, was significantly enhanced in dedifferentiated VSMCs. Furthermore, endogenous BMP-2 antagonists, such as noggin, chordin, and matrix gamma-carboxyglutamic acid protein, were all downregulated in the dedifferentiated VSMCs. Conditioned medium from dedifferentiated VSMCs, but not from redifferentiated VSMCs, stimulated the osteoblastic differentiation of the mesenchymal progenitor C2C12 cells, which was abolished by BMP-2 knockdown. In atherosclerotic intima from apolipoprotein (apo)E-deficient mice, αSM-actin-positive cells, presumably dedifferentiated VSMCs, expressed BMP-2. We generated BMP-2-transgenic mice using αSM-actin promoter and crossed them with apoE-deficient mice (BMP-2-transgenic/apoE-knockout). Significantly accelerated atherosclerotic intimal calcification was detected in BMP-2-transgenic/apoE-knockout mice, although serum lipid concentration and atherosclerotic plaque size were not different from those in apoE-knockout mice. Enhanced calcification appeared to be associated with the frequent emergence of osteoblast-like cells in atherosclerotic intima in BMP-2-transgenic/apoE-knockout mice. Conclusion— Our findings collectively demonstrate an important role of dedifferentiated VSMCs in the pathophysiology of atherosclerotic calcification through activating paracrine BMP-2 osteogenic signals.
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“Furthermore, specific genetic modulation of VSMC osteochondrogenesis in vivo leads to altered calcification in models of atherosclerosis 160-162 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [162]
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Metadata
- Authors
- Nakagawa, Y., Ikeda, K., Akakabe, Y., Koide, M., Uraoka, M., Yutaka, K.-T., Kurimoto-Nakano, R., Takahashi, T., Matoba, S., Yamada, H., Okigaki, M., & Matsubara, H.
- Affiliations
- Kyoto Prefectural University (JP)
- From the Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kamigyo, Kyoto, Japan.
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2010-10
- Volume
- 30
- Issue
- 10
- Pages
- 1908-1915
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2129826616
- Cited by
- 124
- References
- 54
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 3 · 2021: 11 · 2020: 12 · 2019: 7 · 2018: 11 · 2017: 10 · 2016: 8 · 2015: 10 · 2014: 7 · 2013: 11 · 2012: 15
- FWCI
- 4.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Ono Medical Research Foundation
- Japan Heart Foundation
- Japan Society for the Promotion of Science (21590937, 20590885, 18790507)
- 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 › Nephrology › Parathyroid Disorders and Treatments
- Keywords
- BMP-2, vascular calcification, paracrine signaling, osteogenic differentiation, noggin, chordin, osteoblast-like cells, apolipoprotein E deficiency
- MeSH terms
- Animals, Apolipoproteins E, Calcinosis, Cell Differentiation, Cells, Cultured, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Osteoblasts, Osteogenesis, Gene Expression, Culture Media, Conditioned, Tunica Intima, Mice, Knockout, Paracrine Communication, Myocytes, Smooth Muscle, Atherosclerosis, Mice, Cell Dedifferentiation, Bone Morphogenetic Protein 2
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