Dkk1 and Msx2-Wnt7b signaling reciprocally regulate the endothelial-mesenchymal transition in aortic endothelial cells

Su Li Cheng, Jian Su Shao, Abraham Behrmann, Karen Krchma, Dwight A. Towler

Research output: Contribution to journalArticle

60 Scopus citations

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. Approach and 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.

Original languageEnglish (US)
Pages (from-to)1679-1689
Number of pages11
JournalArteriosclerosis, thrombosis, and vascular biology
Volume33
Issue number7
DOIs
StatePublished - Jul 1 2013

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Keywords

  • Dkk1
  • Endothelial cells
  • Fibrosis
  • Mesenchymal transition
  • Wnt signaling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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