title: Endothelial cells modulate osteogenesis in calcifying vascular cells.
abstract: The potential role of vascular endothelium in atherosclerotic calcification is unknown. Endothelial cells (EC) express bone morphogenetic proteins (BMP), and EC-conditioned medium is osteoinductive in marrow stromal cells. To test whether EC are osteoinductive in vascular cells, we used calcifying vascular cells (CVC) that form nodules and mineralize in vitro. We established a coculture model with EC grown opposite CVC on membranes coated with collagen I or collagen IV, both of which are expressed in atherosclerotic lesions. On collagen I, EC did not alter CVC nodule formation, calcification or expression of the osteogenic marker Cbfa1, the chondrogenic marker collagen IX or smooth muscle cell alpha-actin. However, on collagen IV, EC abolished nodule formation and calcification, and expression of cell markers decreased, suggesting dedifferentiation. Matrix GLA protein (MGP), also expressed in atherosclerotic lesions, was added to CVC in coculture. Unexpectedly, MGP enhanced Cbfa1 expression in CVC on both collagen I and IV. The enhancement was most apparent on collagen IV, where calcification also increased. However, MGP did not restore nodule formation on collagen IV, suggesting that nodule formation and cell differentiation are separate processes. The effect of EC on CVC calcification was suppressed by noggin, an inhibitor of BMP activity, and in part mimicked by replacement of EC by BMP-2. Our results support a role for endothelium in vascular calcification, modulated by collagens and MGP.
authors.affiliation: Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Shin
authors.forename: Amina F
authors.initials: AF
authors.lastname: Zebboudj
authors.forename: Kristina
authors.initials: K
authors.lastname: Boström
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000473:pathology* / Q000503:physiopathology; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000494:pharmacology; D002114:Calcinosis / Q000473:pathology* / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology*; D016326:Extracellular Matrix Proteins; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology*; D011506:Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta; D000097568:Matrix Gla Protein; D000099176:Noggin Protein
chemical_list: D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D003094:Collagen; D017077:Culture Media, Conditioned; D016326:Extracellular Matrix Proteins; D011506:Proteins; D016212:Transforming Growth Factor beta; D000097568:Matrix Gla Protein; D000099176:Noggin Protein