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bioRxiv · 10.1101/2022.10.17.512494

Soluble VE-cadherin disrupts endothelial barrier function via VE-PTP/RhoA signalling

Knop, J.-L.·Burkard, N.·Danesh, M.·Dandekar, T.·Srivastava, M.·Hiermaier, M.·Waschke, J.·Flemming, S.·Schlegel, N.
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Abstract

AimIncreased levels of soluble Vascular endothelial (VE)-cadherin fragments (sVE-cadherin) have previously been linked with inflammation-induced loss of endothelial barrier function. We tested whether sVE-cadherin is critically involved in the onset of endothelial barrier dysfunction. Methods and ResultsApplication of recombinant human sVE-cadherin (extracellular domains EC1-5) on human microvascular endothelial cells in vitro and in a rat model in vivo induced loss of endothelial barrier function and reduced microcirculatory flow. sVE-cadherinEC1-5 led to decreased localization of VE-cadherin at cell borders. Additionally, sVE-cadherinEC1-5 perturbed VE-protein tyrosine phosphatase (VE-PTP)/VE-cadherin interaction. VE-PTP inhibitor AKB9778 blunted all sVE-cadherinEC1-5-induced effects in vitro and in vivo. Downstream effects involve VE-PTP-dependent RhoA activation which was attenuated by AKB9778. Rho-kinase inhibitor Y27632 blocked sVE-cadherinEC1-5-induced loss of endothelial barrier function. ConclusionsVE-cadherin disrupts endothelial barrier function by dismantling the VE-cadherin complex at cell borders via VE-PTP-dependent RhoA activation. This uncovers a novel pathophysiological role of sVE-cadherin in the context of endothelial barrier dysfunction in inflammation.

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Knop, J.-L., Burkard, N., Danesh, M., Dandekar, T., Srivastava, M., Hiermaier, M., Waschke, J., Flemming, S., Schlegel, N.. 2022-10-18. Soluble VE-cadherin disrupts endothelial barrier function via VE-PTP/RhoA signalling. https://doi.org/10.1101/2022.10.17.512494

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