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

Abstract

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.

Salidroside Ameliorated Intermittent Hypoxia-Aggravated Endothelial Barrier Disruption and Atherosclerosis via the cAMP/PKA/RhoA Signaling Pathway

“…The adherent junction protein VE-cadherin and tight junction protein ZO-1 are important factors to maintain and regulate endothelial barrier function. CIH can reportedly increase vascular permeability and impair endothelial barrier function by VE-cadherin cleavage ( Makarenko et al, 2014 ; Harki et al, 2021 ). Consistent with previous studies, exposure of HUVECs to IH decreased TEER, increased permeability to FITC-dextran, and suppressed expression of junction proteins VE-cadherin and ZO-1.…”

“…CIH can reportedly increase reactive oxygen species (ROS) generation, which subsequently cause vascular endothelial cadherin (VE-cadherin) cleavage, endothelial barrier injury, and dysfunction ( Makarenko et al, 2014 ; Harki et al, 2021 ). Ras homolog gene family member A (RhoA) and its downstream Rho-associated protein kinase (ROCK) play crucial roles in both oxidative stress and endothelial barrier function ( Shimokawa and Satoh, 2015 ; Komarova et al, 2017 ; Dee et al, 2019 ; Cong and Kong, 2020 ).…”

The Association Between Serum/Plasma Leptin Levels and Obstructive Sleep Apnea Syndrome: A Meta-Analysis and Meta-Regression

“…The results of the present study also showed a moderate positive correlation between leptin concentration and AHI, which supports the above hypothesis. Second, hypoxia is the most important pathophysiological change in patients with OSAS ( 63 ). As AHI increases, oxygen saturation decreases significantly at night and hypoxemia occurs, which causes activation of the sympathetic nervous system, elevated angiotensin levels, and blood pressure fluctuations, all of which can lead to increased plasma leptin levels ( 48 , 64 ).…”

Inhibition of Vascular Endothelial Cadherin Cleavage Prevents Elastic Fiber Alterations and Atherosclerosis Induced by Intermittent Hypoxia in the Mouse Aorta

“…In different situations, VE-cadherin undergoes enzymatic cleavage of its extracellular domain, which then becomes soluble (sVE) and detectable in the blood of patients affected by various cardiovascular comorbidities. This has been reported for OSAS, rheumatoid arthritis and some cancers, suggesting its potential as a biomarker for cardiovascular risk in these pathologies [14][15][16]. VE-cadherin cleavage is activated after phosphorylation of one of its tyrosine residues by the tyrosine kinases Src in response to endothelial cell stimulation by circulating factors such as VEGF, which activates the VEGF receptor tyrosine kinases and TNF-α [15,16].…”

“…We recently demonstrated that IH induces the VE-cadherin cleavage process by pathways that involve reactive oxygen species (ROS), HIF-1, the VEGF receptor (VEGFR) and tyrosine kinases, particularly Src-kinases. This cascade of activation is associated with elevated endothelial permeability in vitro [14]. Actually, endothelial hyperpermeability, a crucial and early step in atherogenesis, could facilitate lipid flux and inflammatory molecule/cell migration across the endothelium [17].…”