TY -的T1 VE-Cadherin睡眠apnoe乳沟a: new insights into intermittent hypoxia-related endothelial permeability JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.04518-2020 SP - 2004518 AU - Harki, Olfa AU - Tamisier, Renaud AU - Pépin, Jean-Louis AU - Bailly, Sébastien AU - Mahmani, Anissa AU - Gonthier, Brigitte AU - Salomon, Aude AU - Vilgrain, Isabelle AU - Faury, Gilles AU - Briançon-Marjollet, Anne Y1 - 2021/01/01 UR - //www.qdcxjkg.com/content/early/2021/02/25/13993003.04518-2020.abstract N2 - Background Obstructive Sleep Apnoea (OSAS) causes intermittent hypoxia (IH) that in turn induces endothelial dysfunction and atherosclerosis progression. We hypothesized that VE-Cadherin cleavage, detected by its released extracellular fragment solubilised in the blood (sVE), may be an early indicator of emergent abnormal endothelial permeability. Our aim was to assess VE-cadherin cleavage in OSAS patients and in in vivo and in vitro IH models to decipher the cellular mechanisms and consequences.Methods Sera from 7 healthy volunteers exposed to fourteen nights of IH, 43 OSAS patients and 31 healthy control subjects were analysed for their sVE content. Human aortic endothelial cells (HAEC) were exposed to 6 h of IH in vitro, with or without an antioxidant or inhibitors of HIF-1, tyrosine kinases or VEGF pathways. VE-Cadherin cleavage and phosphorylation were evaluated, and endothelial permeability was assessed by measuring trans-endothelial electrical resistance (TEER) and FITC-Dextran flux.Results sVE was significantly elevated in sera from healthy volunteers submitted to IH and OSAS patients before treatment, but conversely, decreased in OSAS patients after 6 months of continuous positive airway pressure treatment. OSAS was the main factor accounting for sVE variations in a multivariate analysis. In in vitro experiments, cleavage and expression of VE-Cadherin increased upon HAEC exposure to IH. TEER decreased and FITC-Dextran flux increased. These effects were reversed by all the pharmacological inhibitors tested.Conclusion We suggest that in OSAS, IH increases endothelial permeability in OSAS by inducing VE-Cadherin cleavage through ROS production and activation of HIF-1, VEGF and tyrosine kinase pathways.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Harki has nothing to disclose.Conflict of interest: Dr. Tamisier reports grants, personal fees and other from Agiradom (Healthcare provider), grants and personal fees from Resmed, grants from Inspire, grants from Navigant, grants from Jazz pharmaceuticals, personal fees from Elivie, personal fees from Philips, outside the submitted work; .Conflict of interest: Dr. Pépin reports grants from Air Liquide Foundation, grants and personal fees from Agiradom, grants and personal fees from AstraZeneca, grants from Fisher and Paykel, grants from Mutualia, grants and personal fees from Philips, grants and personal fees from Resmed, grants from Vitalaire,, grants from Boehringer Ingelheim, grants from Jazz Pharmaceuticals, grants from Night Balance, grants from Sefam, all outside the submitted work; .Conflict of interest: Dr. Bailly has nothing to disclose.Conflict of interest: Dr. Mahmani has nothing to disclose.Conflict of interest: Dr. Gonthier has nothing to disclose.Conflict of interest: Dr. Salomon has nothing to disclose.Conflict of interest: Dr. Vilgrain has nothing to disclose.Conflict of interest: Dr. Faury has nothing to disclose.Conflict of interest: Dr. Briançon-Marjollet has nothing to disclose. ER -