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


ABSTRACT: OBJECTIVE:Fluid shear stress intimately regulates vasculogenesis and endothelial homeostasis. The canonical Wnt/?-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 ?-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.

SUBMITTER: Li R 

PROVIDER: S-EPMC4169303 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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

Li Rongsong R   Beebe Tyler T   Jen Nelson N   Yu Fei F   Takabe Wakako W   Harrison Michael M   Cao Hung H   Lee Juhyun J   Yang Hongbo H   Han Peidong P   Wang Kevin K   Shimizu Hirohito H   Chen Jaunian J   Lien Ching-Ling CL   Chi Neil C NC   Hsiai Tzung K TK  

Arteriosclerosis, thrombosis, and vascular biology 20140821 10


<h4>Objective</h4>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.<h4>Approach and results</h4>Oscillatory shear stress upregulated both TOPflash Wnt reporter activities and the ex  ...[more]

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