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

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.

Wnt7a Decreases Brain Endothelial Barrier Function Via β-Catenin Activation

“…These findings contrast with the decrease in TEER values we observed after a 2-day stimulation with Wnt7a. Of note, results similar to ours were observed in a study of human aortic ECs where similar β-catenin mediated increases in permeability were detected [ 57 ].…”

Endothelial mechanobiology under controlled disturbed flows

“…37 Disruption and reduction in VE-Cadherin expression under oscillatory conditions hence suggesta possible redistribution of gap junctions and cytoskeletal proteins that can compromise the monolayer integrity and increase the membrane permeability. 42 Our data suggest that redistribution of cytoskeletal proteins due to bidirectional oscillatory flows mayalterthe membrane permeability and tractional stresses,controlled by ventral stress fibers, to change cell-substrate adhesions. A measurement of the monolayer permeability alone may not represent changes in the mechanobiological behaviors of endothelial cell monolayers.…”

Chronic Lymphocytic Leukemia (CLL)-Derived Extracellular Vesicles Educate Endothelial Cells to Become IL-6-Producing, CLL-Supportive Cells

“…Proteomics analysis indicated that the phosphorylated fraction of β-catenin is significantly upregulated in endothelial cells that were exposed to CLL-exomes; previous studies showed that in these cells, β-catenin binds and activates NFκB [20]. In another study, Rickman et al showed that disturbed flow increases endothelial inflammation and permeability via a Frizzled-4-β-catenin-dependent pathway [34]. This is in line with our ChIP results showing that β-catenin enhances the activity of NFκB in HUVECs.…”