title: Dkk1 and MSX2-Wnt7b signaling reciprocally regulate the endothelial-mesenchymal transition in aortic endothelial cells.
abstract: OBJECTIVE
  Endothelial cells (ECs) can undergo an endothelial-mesenchymal transition with tissue fibrosis. Wnt- and Msx2-regulated signals participate in arteriosclerotic fibrosis and calcification. We studied the impact of Wnt7, Msx2, and Dkk1, a Wnt7 antagonist, on endothelial-mesenchymal transition in primary aortic ECs.
  
  
  RESULTS
  Transduction of aortic ECs with vectors expressing Dkk1 suppressed EC differentiation and induced a mineralizing myofibroblast phenotype. Dkk1 suppressed claudin 5, PECAM, cadherin 5 (Cdh5), Tie1, and Tie2. Dkk1 converted the cuboidal cell monolayer into a spindle-shaped multilayer and inhibited EC cord formation. Myofibroblast and osteogenic markers, SM22, type I collagen, Osx, Runx2, and alkaline phosphatase, were upregulated by Dkk1 via activin-like kinase/Smad pathways. Dkk1 increased fibrotic mineralization of aortic ECs cultured under osteogenic conditions--the opposite of mesenchymal cell responses. Msx2 and Wnt7b maintained morphology and upregulated markers of differentiated ECs. Deleting EC Wnt7b with the Cdh5-Cre transgene in Wnt7b(fl/fl);LDLR(-/-) mice upregulated aortic osteogenic genes (Osx, Sox9, Runx2, and Msx2) and nuclear phospho-Smad1/5, and increased collagen and calcium accumulation.
  
  
  CONCLUSIONS
  Dkk1 enhances endothelial-mesenchymal transition in aortic ECs, whereas Wnt7b and Msx2 signals preserve EC phenotype. EC responses to Dkk1, Wnt7b, and Msx2 are the opposite of mesenchymal responses, coupling EC phenotypic stability with osteofibrogenic predilection during arteriosclerosis.
authors.affiliation: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
authors.forename: Su-Li
authors.initials: SL
authors.lastname: Cheng
authors.forename: Jian-Su
authors.initials: JS
authors.lastname: Shao
authors.forename: Abraham
authors.initials: A
authors.lastname: Behrmann
authors.forename: Karen
authors.initials: K
authors.lastname: Krchma
authors.forename: Dwight A
authors.initials: DA
authors.lastname: Towler
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002417:Cattle; D002454:Cell Differentiation; D048430:Cell Shape; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D009999:Ossification, Heterotopic / Q000378:metabolism; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D014162:Transfection; D051153:Wnt Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; D015820:Cadherins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011973:Receptors, LDL; D051153:Wnt Proteins; D000099152:Cadherin 5; C501127:Dkk1 protein, mouse; C084119:MSX2 protein; C490675:WNT7B protein, human
keywords: Dkk1; Wnt signaling; endothelial cells; fibrosis; mesenchymal transition