Shear Stress-Activated Wnt-Angiopoietin-2 Signaling Recapitulates Vascular Repair in Zebrafish Embryos

Li, R., Beebe, T., Jen, N., Yu, F., Takabe, W., Harrison, M., Cao, H., Lee, J., Yang, H., Han, P., Wang, K., Shimizu, H., Chen, J., Lien, C.L., Chi, N.C., Hsiai, T.K.
Arterioscler. Thromb. Vasc. Biol.   34(10): 2268-75 (Journal)
Registered Authors
Chi, Neil C., Han, Peidong, Harrison, Michael, Lien, Ching-Ling (Ellen), Yang, Hongbo
Wnt signaling pathway, angiopoietin-2, dkk1 protein, zebrafish, zebrafish
MeSH Terms
  • Angiopoietin-2/genetics
  • Angiopoietin-2/metabolism*
  • Animals
  • Animals, Genetically Modified
  • Axin Protein/genetics
  • Axin Protein/metabolism
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Gene Expression Regulation, Developmental
  • Genes, Reporter
  • Green Fluorescent Proteins/genetics
  • Green Fluorescent Proteins/metabolism
  • Human Umbilical Vein Endothelial Cells/metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins/genetics
  • Intercellular Signaling Peptides and Proteins/metabolism
  • Mechanotransduction, Cellular*/drug effects
  • Neovascularization, Physiologic*/drug effects
  • RNA Interference
  • RNA, Messenger/metabolism
  • Stress, Physiological
  • Time Factors
  • Transfection
  • Wnt Signaling Pathway*/drug effects
  • Wnt3A Protein/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
25147335 Full text @ Arterioscler. Thromb. Vasc. Biol.
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.
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.
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.
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