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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.


Matthew Rickman

Mean Ghim

Kuin Pang

Ana Cristina von Huelsen Rocha

Elena M. Drudi

Macià Sureda-Vives

Nicolas Ayoub

Virginia Tajadura-Ortega

Sarah J. George

Peter D. Weinberg

Christina M. Warboys


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.


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,

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
Keywords Cell Biology


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