title: A role for the endothelium in vascular calcification.
abstract: BACKGROUND
  Vascular calcification is a regulated process that involves osteoprogenitor cells and frequently complicates common vascular disease, such as atherosclerosis and diabetic vasculopathy. However, it is not clear whether the vascular endothelium has a role in contributing osteoprogenitor cells to the calcific lesions.
  
  
  OBJECTIVE
  To determine whether the vascular endothelium contributes osteoprogenitor cells to vascular calcification.
  
  
  RESULTS
  In this study, we use 2 mouse models of vascular calcification, mice with gene deletion of matrix Gla protein, a bone morphogenetic protein (BMP)-inhibitor, and Ins2Akita/+ mice, a diabetes model. We show that enhanced BMP signaling in both types of mice stimulates the vascular endothelium to contribute osteoprogenitor cells to the vascular calcification. The enhanced BMP signaling results in endothelial-mesenchymal transitions and the emergence of multipotent cells, followed by osteoinduction. Endothelial markers colocalize with multipotent and osteogenic markers in calcified arteries by immunostaining and fluorescence-activated cell sorting. Lineage tracing using Tie2-Gfp transgenic mice supports an endothelial origin of the osteogenic cells. Enhancement of matrix Gla protein expression in Ins2Akita/+ mice, as mediated by an Mgp transgene, limits the generation of multipotent cells. Moreover, matrix Gla protein-depleted human aortic endothelial cells in vitro acquire multipotency rendering the cells susceptible to osteoinduction by BMP and high glucose.
  
  
  CONCLUSIONS
  Our data suggest that the endothelium is a source of osteoprogenitor cells in vascular calcification that occurs in disorders with high BMP activation, such as deficiency of BMP-inhibitors and diabetes mellitus.
authors.affiliation: Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. yyao@mednet.ucla.edu
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Yao
authors.forename: Medet
authors.initials: M
authors.lastname: Jumabay
authors.forename: Albert
authors.initials: A
authors.lastname: Ly
authors.forename: Melina
authors.initials: M
authors.lastname: Radparvar
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cubberly
authors.forename: Kristina I
authors.initials: KI
authors.lastname: Boström
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002114:Calcinosis / Q000503:physiopathology*; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019070:Cell Lineage; D054338:Cell Transdifferentiation / Q000502:physiology*; D002478:Cells, Cultured / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D003925:Diabetic Angiopathies / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology*; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology; D006579:Heterozygote; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000502:physiology; D039902:Multipotent Stem Cells / Q000473:pathology*; D009124:Muscle Proteins / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D042787:Receptor, TIE-2 / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D014652:Vascular Diseases / Q000503:physiopathology*; D000097568:Matrix Gla Protein
chemical_list: D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D005947:Glucose; D007328:Insulin; D008840:Microfilament Proteins; D009124:Muscle Proteins; D034741:RNA, Small Interfering; D042787:Receptor, TIE-2; D011993:Recombinant Fusion Proteins; D000097568:Matrix Gla Protein; C561967:Ins2 protein, mouse; C058992:Tagln protein, mouse; C079086:Tek protein, mouse
keywords: bone morphogenetic protein; endothelium; matrix Gla protein; progenitor cells; vascular calcification