title: SLUG is expressed in endothelial cells lacking primary cilia to promote cellular calcification.
abstract: OBJECTIVE
  Arterial calcification is considered a major cause of death and disabilities worldwide because the associated vascular remodeling leads to myocardial infarction, stroke, aneurysm, and pulmonary embolism. This process occurs via poorly understood mechanisms involving a variety of cell types, intracellular mediators, and extracellular cues within the vascular wall. An inverse correlation between endothelial primary cilia and vascular calcified areas has been described although the signaling mechanisms involved remain unknown. We aim to investigate the signaling pathways regulated by the primary cilium that modulate the contribution of endothelial cells to vascular calcification.
  
  
  RESULTS
  We found that human and murine endothelial cells lacking primary cilia are prone to undergo mineralization in response to bone morphogenetic proteins stimulation in vitro. Using the Tg737(orpk/orpk) cillium-defective mouse model, we show that nonciliated aortic endothelial cells acquire the ability to transdifferentiate into mineralizing osteogenic cells, in a bone morphogenetic protein-dependent manner. We identify β-CATENIN-induced SLUG as a key transcription factor controlling this process. Moreover, we show that the endothelial expression of SLUG is restricted to atheroprone areas in the aorta of LDLR(-/-) mice. Finally, we demonstrate that SLUG and phospho-homolog of the Drosophila protein, mothers against decapentaplegic (MAD) and the Caenorhabditis elegans protein SMA (from gene sma for small body size)-1/5/8 expression increases in endothelial cells constituting the vasa vasorum in the human aorta during the progression toward atherosclerosis.
  
  
  CONCLUSIONS
  We demonstrated that the lack of primary cilia sensitizes the endothelium to undergo bone morphogenetic protein-dependent-osteogenic differentiation. These data emphasize the role of the endothelial cells on the vascular calcification and uncovers SLUG as a key target in atherosclerosis.
authors: From the Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands (G.S.-D., A.G.d.V., M.-J.G., P.t.D.), Department of Vascular Surgery (J.H.L., A.M.-S.) and Department of Anatomy and Embryology (M.C.D., C.V.M., B.P.H.), Leiden University Medical Center, Leiden, The Netherlands. G.Sanchez_Duffhues@lumc.nl P.ten_Dijke@lumc.nl.
authors: Gonzalo
authors: G
authors: Sánchez-Duffhues
authors: From the Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands (G.S.-D., A.G.d.V., M.-J.G., P.t.D.), Department of Vascular Surgery (J.H.L., A.M.-S.) and Department of Anatomy and Embryology (M.C.D., C.V.M., B.P.H.), Leiden University Medical Center, Leiden, The Netherlands.
authors: Amaya García
authors: AG
authors: de Vinuesa
authors: From the Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands (G.S.-D., A.G.d.V., M.-J.G., P.t.D.), Department of Vascular Surgery (J.H.L., A.M.-S.) and Department of Anatomy and Embryology (M.C.D., C.V.M., B.P.H.), Leiden University Medical Center, Leiden, The Netherlands.
authors: Jan H
authors: JH
authors: Lindeman
authors: From the Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands (G.S.-D., A.G.d.V., M.-J.G., P.t.D.), Department of Vascular Surgery (J.H.L., A.M.-S.) and Department of Anatomy and Embryology (M.C.D., C.V.M., B.P.H.), Leiden University Medical Center, Leiden, The Netherlands.
authors: Adri
authors: A
authors: Mulder-Stapel
authors: From the Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands (G.S.-D., A.G.d.V., M.-J.G., P.t.D.), Department of Vascular Surgery (J.H.L., A.M.-S.) and Department of Anatomy and Embryology (M.C.D., C.V.M., B.P.H.), Leiden University Medical Center, Leiden, The Netherlands.
authors: Marco C
authors: MC
authors: DeRuiter
authors: From the Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands (G.S.-D., A.G.d.V., M.-J.G., P.t.D.), Department of Vascular Surgery (J.H.L., A.M.-S.) and Department of Anatomy and Embryology (M.C.D., C.V.M., B.P.H.), Leiden University Medical Center, Leiden, The Netherlands.
authors: Conny
authors: C
authors: Van Munsteren
authors: From the Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands (G.S.-D., A.G.d.V., M.-J.G., P.t.D.), Department of Vascular Surgery (J.H.L., A.M.-S.) and Department of Anatomy and Embryology (M.C.D., C.V.M., B.P.H.), Leiden University Medical Center, Leiden, The Netherlands.
authors: Marie-José
authors: MJ
authors: Goumans
authors: From the Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands (G.S.-D., A.G.d.V., M.-J.G., P.t.D.), Department of Vascular Surgery (J.H.L., A.M.-S.) and Department of Anatomy and Embryology (M.C.D., C.V.M., B.P.H.), Leiden University Medical Center, Leiden, The Netherlands.
authors: Beerend P
authors: BP
authors: Hierck
authors: From the Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands (G.S.-D., A.G.d.V., M.-J.G., P.t.D.), Department of Vascular Surgery (J.H.L., A.M.-S.) and Department of Anatomy and Embryology (M.C.D., C.V.M., B.P.H.), Leiden University Medical Center, Leiden, The Netherlands. G.Sanchez_Duffhues@lumc.nl P.ten_Dijke@lumc.nl.
authors: Peter
authors: P
authors: Ten Dijke
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D002923:Cilia; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis; D010766:Phosphorylation; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics; D061205:Vascular Calcification / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; C495267:CTNNB1 protein, mouse; D011973:Receptors, LDL; C000604407:SNAI1 protein, human; D051896:Smad Proteins, Receptor-Regulated; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; C490898:Tg737Rpw protein, mouse; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; C000604451:sna protein, Drosophila
keywords: BMP receptor; atherosclerosis; cilia; transforming growth factors-β