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

Rongsong Li, Tyler Beebe, Nelson Jen, Fei Yu, Wakako Takabe, Michael Harrison, Hung Cao, Juhyun Lee, Hongbo Yang, Peidong Han, Kevin Wang, Hirohito Shimizu, Jaunian Chen, Ching Ling Lien, Neil C. Chi, Tzung K. Hsiai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2268-2275
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume34
Issue number10
DOIs
StatePublished - Oct 1 2014
Externally publishedYes

Keywords

  • Angiopoietin-2
  • DKK-1/dickkopfs-1
  • Endothelial repairs
  • Human aortic endothelial cells (HAEC)
  • Vasculogenesis
  • Wnt signaling
  • Zebrafish

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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