BackgroundObstructive 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.MethodsSera 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.ResultssVE 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.ConclusionWe 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.

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