Pro-inflammatory role of Wnt/β-catenin signaling in endothelial dysfunction

Kerry S Wadey*, Alexandros Somos, Genevieve Leyden, Hazel Blythe, Jeremy Chan, Lawrence Hutchinson, Alastair Poole, Aleksandra Frankow, Jason L Johnson, Sarah J George

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

7 Citations (Scopus)

Abstract

Background: Endothelial dysfunction is a critical component of both atherosclerotic plaque formation and saphenous vein graft failure. Crosstalk between the pro-inflammatory TNF-α-NFκB signaling axis and the canonical Wnt/β-catenin signaling pathway potentially plays an important role in regulating endothelial dysfunction, though the exact nature of this is not defined.

Results: In this study, cultured endothelial cells were challenged with TNF-α and the potential of a Wnt/β-catenin signaling inhibitor, iCRT-14, in reversing the adverse effects of TNF-α on endothelial physiology was evaluated. Treatment with iCRT-14 lowered nuclear and total NFκB protein levels, as well as expression of NFκB target genes, IL-8 and MCP-1. Inhibition of β-catenin activity with iCRT-14 suppressed TNF-α-induced monocyte adhesion and decreased VCAM-1 protein levels. Treatment with iCRT-14 also restored endothelial barrier function and increased levels of ZO-1 and focal adhesion-associated phospho-paxillin (Tyr118). Interestingly, inhibition of β-catenin with iCRT-14 enhanced platelet adhesion in cultured TNF-α-stimulated endothelial cells and in an ex vivo human saphenous vein model, most likely via elevating levels of membrane-tethered vWF. Wound healing was moderately retarded by iCRT-14; hence, inhibition of Wnt/β-catenin signaling may interfere with re-endothelialisation in grafted saphenous vein conduits.

Conclusion: Inhibition of the Wnt/β-catenin signaling pathway with iCRT-14 significantly recovered normal endothelial function by decreasing inflammatory cytokine production, monocyte adhesion and endothelial permeability. However, treatment of cultured endothelial cells with iCRT-14 also exerted a pro-coagulatory and moderate anti-wound healing effect: these factors may affect the suitability of Wnt/β-catenin inhibition as a therapy for atherosclerosis and vein graft failure.
Original languageEnglish
Article number1059124
Number of pages16
JournalFrontiers in Cardiovascular Medicine
Volume9
DOIs
Publication statusPublished - 17 Jan 2023

Bibliographical note

Copyright © 2023 Wadey, Somos, Leyden, Blythe, Chan, Hutchinson, Poole, Frankow, Johnson and George.

Keywords

  • atherosclerosis
  • endothelium
  • monocyte
  • NFκB
  • permeability
  • platelet
  • TNF-α
  • Wnt/β-catenin

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