Intermittent hypoxia increases VE-Cadherin cleavage in OSAS through ROS and HIF-1 pathways

Abstract

Obstructive Sleep Apnea syndrome (OSAS), characterized by intermittent hypoxia (IH) cycles during sleep, induces endothelial dysfunction and atherogenesis lesions, which could be mediated by an increase in endothelial permeability. VE-Cadherin (VECad) cleavage, detected by the soluble extracellular fragment released (sVE), may be a key step in this regulation of endothelial permeability. Our aim was to search for sVE in sera from healthy volunteers submitted to IH, and from OSAS patients before and after treatment by continuous positive airway pressure (CPAP) and to characterize mechanisms regulating VECad cleavage in endothelial cells submitted to IH. sVE was searched in sera from 7 healthy volunteers exposed to IH, 44 OSAS patients and 31 control subjects. Human Aortic Endothelial Cells (HAEC) were exposed to 6 hours of IH in vitro, then endothelial permeability was assessed by measuring trans-endothelial electrical resistance (TEER) and VECad cleavage was evaluated by detecting sVE in cells supernatants after treatment by IH and tyrosine kinase inhibitor (30 μM Genistein or 10 μM PP2), HIF-1 inhibitor (1 μM 2-Methoxyestradiol), an anti-oxidant (100 μM Tempol) or anti-hVEGF blocking antibody (0.5 μg/mL). sVE was significantly elevated in healthy volunteers submitted to IH and in OSAS patient sera before treatment, but decreased in OSAS patients after 6 months of CPAP therapy. We found a significant positive correlation between sVE and OSAS severity and between sVE and serum VEGF. In HAEC supernatants, TEER decreased by 37.5% and sVE increased by 39% after cell exposure to IH. These effects were reversed by all the pharmacological inhibitors tested. we suggest that, in OSAS, IH increases endothelial permeability by inducing VECad cleavage via the ROS, HIF1, VEGF and tyrosine kinase pathways. Future studies will determine whether sVE could be a potential biomarker to evaluate early endothelial alterations in OSAS.