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BackgroundObstructive 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.MethodsSera 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.ResultssVE 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.ConclusionsWe 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.

In the arteries of vertebrates, evolution has given rise to resilient macromolecular structures, elastin and elastic fibers, capable of sustaining an elevated blood pressure and smoothening the discontinuous blood flow and pressure generated by the heart. Elastic fibers are produced only during development and childhood, before being progressively degraded by mechanical stress and enzymatic activities during adulthood and aging. During this period, arterial elastic fiber calcification and loading of lipids also occur, all of these events conducting to arteriosclerosis. This leads to a progressive dysfunction of the large elastic arteries inducing elevated blood pressure as well as altered hemodynamics and organ perfusion, which induce more global malfunctions of the body during normal aging. Additionally, some arterial conditions occur more frequently with advancing age, such as atherosclerosis or aneurysms, which are called age-related diseases or pathological aging. The physiological or pathological degradation of elastic fibers and function of elastic arteries seemed to be rather inevitable over time. However, during the recent years, different molecules - including several ATP-dependent potassium channel openers, such as minoxidil - have been shown to re-induce elastin production and elastic fiber assembly, leading to improvements in the arterial structure and function or in organ perfusion. This review summarizes the changes in the arterial elastic fibers and structure from development until aging, and presents some of the potential pharmacotherapies leading to elastic fiber neosynthesis and arterial function improvement.

Background 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. Objective 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. Methods 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). Results 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. Conclusion 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.