title: Paracrine osteogenic signals via bone morphogenetic protein-2 accelerate the atherosclerotic intimal calcification in vivo.
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.
  
  
  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.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kamigyo, Kyoto, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Koji
authors.initials: K
authors.lastname: Ikeda
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Akakabe
authors.forename: Masahiro
authors.initials: M
authors.lastname: Koide
authors.forename: Maki
authors.initials: M
authors.lastname: Uraoka
authors.forename: Ko-Taro
authors.initials: KT
authors.lastname: Yutaka
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Kurimoto-Nakano
authors.forename: Tomosaburo
authors.initials: T
authors.lastname: Takahashi
authors.forename: Satoaki
authors.initials: S
authors.lastname: Matoba
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamada
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Okigaki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsubara
mesh_terms: 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
chemical_list: D001057:Apolipoproteins E; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D017077:Culture Media, Conditioned