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

Abstract Aim Increased 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 Results Application 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-cadherin EC1-5 led to decreased localization of VE-cadherin at cell borders. Additionally, sVE-cadherin EC1-5 perturbed VE-protein tyrosine phosphatase (VE-PTP)/VE-cadherin interaction. VE-PTP inhibitor AKB9778 blunted all sVE-cadherin EC1-5 -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-cadherin EC1-5 -induced loss of endothelial barrier function. Conclusion sVE-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.