Paracrine osteogenic signals via bone morphogenetic protein-2 accelerate the atherosclerotic intimal calcification in vivo.
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.


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.


CONCLUSIONS
Our findings collectively demonstrate an important role of dedifferentiated VSMCs in the pathophysiology of atherosclerotic calcification through activating paracrine BMP-2 osteogenic signals.
Nakagawa
Yusuke
Y
Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kamigyo, Kyoto, Japan.
Ikeda
Koji
K
Akakabe
Yoshiki
Y
Koide
Masahiro
M
Uraoka
Maki
M
Yutaka
Ko-Taro
KT
Kurimoto-Nakano
Ritsuko
R
Takahashi
Tomosaburo
T
Matoba
Satoaki
S
Yamada
Hiroyuki
H
Okigaki
Mitsuhiko
M
Matsubara
Hiroaki
H
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000502:physiology*; D002114:Calcinosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D054337:Cell Dedifferentiation; D002454:Cell Differentiation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000473:pathology / Q000502:physiology; D010006:Osteoblasts / Q000473:pathology / Q000502:physiology; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*; D019899:Paracrine Communication; D017539:Tunica Intima / Q000473:pathology / Q000503:physiopathology
D001057:Apolipoproteins E; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D017077:Culture Media, Conditioned