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

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.

• Authors: Olfa Harki, Renaud Tamisier, Jean-Louis Pépin, Sébastien Bailly, Anissa Mahmani, Brigitte Gonthier, Aude Salomon, Isabelle Vilgrain, Gilles Faury, Anne Briançon-Marjollet
• Journal: The European respiratory journal (Eur Respir J) Vol. 58 Issue 4 (10 2021) ISSN: 1399-3003 [Electronic] England
• PMID: 33737411 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright ©The authors 2021. For reproduction rights and permissions contact [email protected].

Chemical References

• Antigens, CD
• Cadherins
• Vascular Endothelial Growth Factor A
• cadherin 5

Topics

• Antigens, CD
• Cadherins (metabolism)
• Capillary Permeability
• Endothelial Cells (metabolism)
• Humans
• Hypoxia
• Permeability
• Sleep Apnea, Obstructive
• Vascular Endothelial Growth Factor A