Cited by 124Atherosclerosis and Cardiovascular DiseasesDermatological and Skeletal DisordersParathyroid Disorders and Treatments

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Paracrine Osteogenic Signals via Bone Morphogenetic Protein-2 Accelerate the Atherosclerotic Intimal Calcification In Vivo

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Nakagawa, Yusuke, Ikeda, Koji, Akakabe, Yoshiki, Koide, Masahiro, Uraoka, Maki, Yutaka, Ko-taro, Kurimoto-Nakano, Ritsuko, Takahashi, Tomosaburo, Matoba, Satoaki, Yamada, Hiroyuki, Okigaki, Mitsuhiko, Matsubara, Hiroaki·2010·Arteriosclerosis, Thrombosis, and Vascular Biology

DOI 10.1161/atvbaha.110.206185

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Abstract

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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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.
ORCID: Ikeda, Koji
Koide, Masahiro
Matoba, Satoaki
Yamada, Hiroyuki
Matsubara, Hiroaki
Venue: Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2010-10
Volume: 30
Issue: 10
Pages: 1908-1915
ISSN: 1079-5642 (ISSN-L)
1524-4636
DOI: 10.1161/atvbaha.110.206185
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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Paracrine Osteogenic Signals via Bone Morphogenetic Protein-2 Accelerate the Atherosclerotic Intimal Calcification In Vivo

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