Dkk1 and Msx2–Wnt7b Signaling Reciprocally Regulate the Endothelial–Mesenchymal Transition in Aortic Endothelial Cells

Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 33 Số 7 - Trang 1679-1689 - 2013
Su‐Li Cheng1,2, Jian-Su Shao1,2, Abraham Behrmann1,2, Karen Krchma1,2, Dwight A. Towler1,2
1Department of Internal Medicine, Washington University, St. Louis, MO (J.-S.S.).
2From the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL (S.-L.C., A.B., K.K., D.A.T.); and Department of Internal Medicine, Washington University, St. Louis, MO (J.-S.S.).

Tóm tắt

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.

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Tài liệu tham khảo

10.1002/path.2101

10.1016/j.jacc.2006.12.050

10.1161/circresaha.110.234278

10.1172/JCI24140

10.1161/atvbaha.107.153668

10.1161/circresaha.110.219899

10.1074/jbc.M800851200

10.1002/dvdy.21619

10.1002/dvdy.20939

10.1016/j.ydbio.2009.11.030

10.1161/atvbaha.110.216184

10.1002/jcp.22322

10.1038/nm.2252

10.1016/j.ajpath.2011.06.001

10.1186/1471-213X-8-75

10.1038/nature02028

10.1073/pnas.1106954108

10.1074/jbc.M306972200

10.1126/science.1164594

10.1359/jbmr.081235

10.1007/BF01002528

Ponce ML. In vitro matrigel angiogenesis assays.Methods Mol Med. 2001;46:205–209.

10.1091/mbc.9.4.701

10.1073/pnas.94.12.6273

10.1161/circresaha.110.229955

10.1161/atvbaha.109.197582

10.1172/JCI42040

10.1002/hep.22764

10.1152/ajpcell.00419.2009

10.1124/jpet.106.117051

10.1359/jbmr.2002.17.1.15

10.1073/pnas.142063399

10.1177/17.2.110

10.1016/j.bbrc.2011.04.029

10.7150/ijbs.4488

10.1006/bbrc.1997.7325

10.1002/jbmr.348

10.1016/j.yjmcc.2009.01.005

10.1161/01.res.0000190604.90049.71

10.1038/nchembio.2007.54

10.1002/dvdy.20643

10.1242/dev.015495

10.1161/circresaha.110.221531

10.1161/circresaha.110.223750

10.1016/j.jacc.2006.02.040

10.1161/circulationaha.111.040337

10.1016/j.ijcard.2010.04.007

10.1172/JCI42556

10.1016/j.ydbio.2008.09.012

10.1128/MCB.22.17.6100-6110.2002

10.1161/atvbaha.109.189761

10.1161/01.res.0000132747.12860.10

10.1016/j.bbrc.2009.12.027

10.1681/ASN.2008101059

10.1161/circresaha.110.236596

10.1126/stke.18pe10

10.1161/CIRCRESAHA.107.171025

10.4103/2045-8932.94817

10.1161/circresaha.108.179465

10.1038/nature03928

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Thông tin xuất bản

Arteriosclerosis, Thrombosis, and Vascular Biology

Tập 33 Số 7

1679-1689

Thông tin tác giả