Regulation of in vitro vascular calcification by BMP4, VEGF and Wnt3a.
Vascular calcification is a common clinical complication of cardiovascular disease, diabetes and end-stage renal failure, associated with significant morbidity and mortality. In this study we demonstrate that factors secreted by the hypertrophic chondrocytes induce matrix mineralization and osteoblastic transformation in cultured mouse vascular smooth muscle cells (VSMCs). In addition, these factors render VSMCs responsive to BMP4 and Wnt3a ligands. Neither BMP-4 nor Wnt3a could induce mineralization in short-term (up to 8 days) cultures of primary mouse VSMCs. However, both ligands act synergistically with the chondrocyte-conditioned medium causing a further increase in VSMC calcification. Finally, we show that commitment of VSMCs towards the BMP-regulated mineralization can be induced by the chondrocyte-secreted bone anabolic factor VEGF. In addition, expression profiling suggests a novel role in vascular calcification for the matrix proteins previously known to regulate bone formation and mineralization (including MMP3, fibulin, 11betahydroxysteroid dehydrogenase 1 and retinoic acid receptor responder 2). The results of this study may contribute to further understanding of the cellular mechanisms responsible for vascular calcification and provide important information for the treatment of this pathology.
Mikhaylova
Lyudmila
L
Department of Anatomy and Cell Biology, School of Medicine, Tufts University, Boston, MA 02111, USA.
Malmquist
Jennifer
J
Nurminskaya
Maria
M
D000818:Animals; D001158:Arteries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D001857:Bone Matrix / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000502:physiology; D002114:Calcinosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; C467480:vascular endothelial growth factor A, mouse