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

Background: Endothelial dysfunction is a critical component of both atherosclerotic plaque formation and saphenous vein graft failure. Crosstalk between the pro-inflammatory TNF-alpha-NF kappa B signaling axis and the canonical Wnt/beta-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-alpha and the potential of a Wnt/beta-catenin signaling inhibitor, iCRT-14, in reversing the adverse effects of TNF-alpha on endothelial physiology was evaluated. Treatment with iCRT-14 lowered nuclear and total NF kappa B protein levels, as well as expression of NF kappa B target genes, IL-8 and MCP-1. Inhibition of beta-catenin activity with iCRT-14 suppressed TNF-alpha-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 beta-catenin with iCRT-14 enhanced platelet adhesion in cultured TNF-alpha-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/beta-catenin signaling may interfere with re-endothelialisation in grafted saphenous vein conduits.Conclusion: Inhibition of the Wnt/beta-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/beta-catenin inhibition as a therapy for atherosclerosis and vein graft failure.