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 VL - 58 IS - 4 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 - 2021/10/01 UR - //www.qdcxjkg.com/content/58/4/2004518.abstract N2 - Background Obstructive sleep apnoea (OSA) causes intermittent hypoxia that in turn induces endothelial dysfunction and atherosclerosis progression. We hypothesised 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 OSA patients and in in vivo and in vitro intermittent hypoxia models to decipher the cellular mechanisms and consequences.Methods Sera from seven healthy volunteers exposed to 14 nights of intermittent hypoxia, 43 OSA patients and 31 healthy control subjects were analysed for their sVE content. Human aortic endothelial cells (HAECs) were exposed to 6 h of intermittent hypoxia in vitro, with or without an antioxidant or inhibitors of hypoxia-inducible factor (HIF)-1, tyrosine kinases or vascular endothelial growth factor (VEGF) pathways. VE-cadherin cleavage and phosphorylation were evaluated, and endothelial permeability was assessed by measuring transendothelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC)–dextran flux.Results sVE was significantly elevated in sera from healthy volunteers submitted to intermittent hypoxia and OSA patients before treatment, but conversely decreased in OSA patients after 6 months of continuous positive airway pressure treatment. OSA 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 intermittent hypoxia. TEER decreased and FITC–dextran flux increased. These effects were reversed by all of the pharmacological inhibitors tested.Conclusions We suggest that in OSA, intermittent hypoxia increases endothelial permeability in OSA by inducing VE-cadherin cleavage through reactive oxygen species production, and activation of HIF-1, VEGF and tyrosine kinase pathways.This study demonstrates for the first time that VE-cadherin is cleaved in sleep apnoea patients, in volunteers exposed to 14 nights of intermittent hypoxia and in endothelial cells exposed to in vitro intermittent hypoxia, leading to increased endothelial permeability https://bit.ly/3sAy5sc ER -