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Arterioscler Thromb Vasc Biol. 2014 Oct;34(10):2268-75. doi: 10.1161/ATVBAHA.114.303345. Epub 2014 Aug 21.

Shear stress-activated Wnt-angiopoietin-2 signaling recapitulates vascular repair in zebrafish embryos.

Author information

1
From the Department of Medicine, School of Medicine (R.L., T.K.H.), Department of Bioengineering (T.B., N.J., F.Y., W.T., H.C., J.L., T.K.H.), and Department of Molecular, Cell, and Developmental Biology (K.W., H.S., J.C.), University of California, Los Angeles; Department of Surgery, Children's Hospital Los Angeles, CA (M.H., C.-L.L.); and Division of Cardiology, Department of Medicine, School of Medicine (H.Y., P.H., N.C.C.) and Institute of Genomic Medicine (N.C.C.), University of California, San Diego, La Jolla.
2
From the Department of Medicine, School of Medicine (R.L., T.K.H.), Department of Bioengineering (T.B., N.J., F.Y., W.T., H.C., J.L., T.K.H.), and Department of Molecular, Cell, and Developmental Biology (K.W., H.S., J.C.), University of California, Los Angeles; Department of Surgery, Children's Hospital Los Angeles, CA (M.H., C.-L.L.); and Division of Cardiology, Department of Medicine, School of Medicine (H.Y., P.H., N.C.C.) and Institute of Genomic Medicine (N.C.C.), University of California, San Diego, La Jolla. thsiai@mednet.ucla.edu.

Abstract

OBJECTIVE:

Fluid shear stress intimately regulates vasculogenesis and endothelial homeostasis. The canonical Wnt/β-catenin signaling pathways play an important role in differentiation and proliferation. In this study, we investigated whether shear stress activated angiopoietin-2 (Ang-2) via the canonical Wnt signaling pathway with an implication in vascular endothelial repair.

APPROACH AND RESULTS:

Oscillatory shear stress upregulated both TOPflash Wnt reporter activities and the expression of Ang-2 mRNA and protein in human aortic endothelial cells accompanied by an increase in nuclear β-catenin intensity. Oscillatory shear stress-induced Ang-2 and Axin-2 mRNA expression was downregulated in the presence of a Wnt inhibitor, IWR-1, but was upregulated in the presence of a Wnt agonist, LiCl. Ang-2 expression was further downregulated in response to a Wnt signaling inhibitor, DKK-1, but was upregulated by Wnt agonist Wnt3a. Both DKK-1 and Ang-2 siRNA inhibited endothelial cell migration and tube formation, which were rescued by human recombinant Ang-2. Both Ang-2 and Axin-2 mRNA downregulation was recapitulated in the heat-shock-inducible transgenic Tg(hsp70l:dkk1-GFP) zebrafish embryos at 72 hours post fertilization. Ang-2 morpholino injection of Tg (kdrl:GFP) fish impaired subintestinal vessel formation at 72 hours post fertilization, which was rescued by zebrafish Ang-2 mRNA coinjection. Inhibition of Wnt signaling with IWR-1 also downregulated Ang-2 and Axin-2 expression and impaired vascular repair after tail amputation, which was rescued by zebrafish Ang-2 mRNA injection.

CONCLUSIONS:

Shear stress activated Ang-2 via canonical Wnt signaling in vascular endothelial cells, and Wnt-Ang-2 signaling is recapitulated in zebrafish embryos with a translational implication in vascular development and repair.

KEYWORDS:

DKK-1/dickkopfs-1; Wnt signaling; angiopoietin-2; endothelial repairs; human aortic endothelial cells (HAEC); vasculogenesis; zebrafish

PMID:
25147335
PMCID:
PMC4169303
DOI:
10.1161/ATVBAHA.114.303345
[Indexed for MEDLINE]
Free PMC Article

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