Disturbed flow increases endothelial inflammation and permeability via a Frizzled-4-β-catenin-dependent pathway

Rickman, Matthew; Ghim, Mean; Pang, Kuin; von Huelsen Rocha, Ana Cristina; Drudi, Elena M.; Sureda-Vives, Macià; Ayoub, Nicolas; Tajadura-Ortega, Virginia; George, Sarah J.; Weinberg, Peter D.; Warboys, Christina M.

Abstract

Multidirectional or disturbed flow promotes endothelial dysfunction and is associated with early atherogenesis. Here we investigated the role of Wnt signalling in flow-mediated endothelial dysfunction. The expression of Frizzled-4 was higher in cultured human aortic endothelial cells (EC) exposed to disturbed rather than undisturbed flow, obtained using an orbital shaker. Increased expression was also detected in regions of the porcine aortic arch exposed to disturbed flow. The increased Frizzled-4 expression in cultured EC was abrogated following knockdown of R-spondin-3. Disturbed flow also increased the nuclear localisation and activation of β-catenin, an effect that was dependent on Frizzled-4 and R-spondin-3. Inhibition of β-catenin using iCRT5, or knockdown of Frizzled-4 or R-spondin-3, resulted in reduced expression of pro-inflammatory genes in EC exposed to disturbed flow, as did inhibition of WNT5A signalling. Inhibition of the canonical Wnt pathway had no effect. Inhibition of β-catenin also reduced endothelial paracellular permeability; this was associated with altered junctional and focal adhesion organisation and cytoskeletal remodelling. These data suggest the presence of an atypical Frizzled-4-β-catenin pathway that promotes endothelial dysfunction in response to disturbed flow.

Citation

Rickman, M., Ghim, M., Pang, K., von Huelsen Rocha, A. C., Drudi, E. M., Sureda-Vives, M., …Warboys, C. M. (in press). Disturbed flow increases endothelial inflammation and permeability via a Frizzled-4-β-catenin-dependent pathway. Journal of Cell Science, https://doi.org/10.1242/jcs.260449

• Journal Article Type: Article
• Acceptance Date: Feb 19, 2023
• Deposit Date: Mar 1, 2023
• Publicly Available Date: Mar 2, 2023
• Journal: Journal of Cell Science
• Print ISSN: 0021-9533
• Electronic ISSN: 1477-9137
• Publisher: The Company of Biologists
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1242/jcs.260449
• Keywords: Cell Biology