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. 2021 Oct 7;58(4):2004518.
doi: 10.1183/13993003.04518-2020. Print 2021 Oct.

VE-cadherin cleavage in sleep apnoea: new insights into intermittent hypoxia-related endothelial permeability

Olfa Harki  1 , Renaud Tamisier  1 , Jean-Louis Pépin  1 , Sébastien Bailly  1 , Anissa Mahmani  1 , Brigitte Gonthier  1 , Aude Salomon  2 , Isabelle Vilgrain  2 , Gilles Faury  1 , Anne Briançon-Marjollet  3
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Free article

VE-cadherin cleavage in sleep apnoea: new insights into intermittent hypoxia-related endothelial permeability

Olfa Harki et al. Eur Respir J. .
Free article

Abstract

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.

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Conflict of interest statement

Conflict of interest: O. Harki has nothing to disclose. Conflict of interest: R. Tamisier reports grants, personal fees for lectures and other (travel grants) from Agiradom (Healthcare provider), grants and personal fees from ResMed, grants from Inspire, Navigant and Jazz Pharmaceuticals, personal fees for lectures from Elivie and Philips, outside the submitted work. Conflict of interest: J-L. Pépin reports grants and personal fees from Agiradom, AstraZeneca, Philips and ResMed, grants from Air Liquide Foundation, Fisher and Paykel, Mutualia, Vitalaire, Boehringer Ingelheim, Jazz Pharmaceuticals, Night Balance and Sefam, all outside the submitted work. Conflict of interest: S. Bailly has nothing to disclose. Conflict of interest: A. Mahmani has nothing to disclose. Conflict of interest: B. Gonthier has nothing to disclose. Conflict of interest: A. Salomon has nothing to disclose. Conflict of interest: I. Vilgrain has nothing to disclose. Conflict of interest: G. Faury has nothing to disclose. Conflict of interest: A. Briançon-Marjollet has nothing to disclose.

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