VE-cadherin cleavage in obstructive sleep apnea syndrome: Signalling pathway and proteases as anti-atherogenic targets

Cardiovascular complications of obstructive sleep apnea syndrome (OSA), such as atherosclerosis, are a real public health concern. They result from endothelial dysfunction induced by intermittent hypoxia (IH). VE-cadherin (VE-cad) undergoes IH-induced cleavage leading to be a biomarker of endothelial dysfunction in several pathologies (sVE). Our hypothesis is that, in OSA, VE-cad cleavage would contribute to the onset of endothelial permeability, resulting in endothelial dysfunction and atherosclerosis. Our aim is to characterize the signalling pathway and proteases that perform VE-cad cleavage in a cellular model of IH and determine if blocking VE-cad cleavage in vitro and in vivo could inhibit IH-induced atherogenesis. Human Aortic Endothelial Cells (HAEC) monolayers were exposed to 6 h IH and treated with tyr-kinase inhibitors (Saracatinib, Pazopanib), HIF-1 inhibitor (Acriflavine) and protease's inhibitors. Candidate proteases (MMP2, PCSK9 and ADAM10) were identified by performing a human protease array in OSA patient's sera. Endothelial permeability was assessed by measuring FITC-Dextran permeability and monocyte passage. VE-cad cleavage was studied by measuring sVE in cells’ supernatants. Vascular remodeling and VE-cad regulation were studied in C57BL/6 mice (2 weeks IH), atherosclerotic plaques and arterial pressure were studied in ApoE-/- mice (8 weeks IH), both treated with tyr-kinase and HIF-1 inhibitors. In our IH cellular model, VE-cad cleavage and endothelial permeability increased. These effects were reversed by the HIF-1 and tyr-kinase inhibitors and the proteases’ inhibitors. In vivo, IH increased aorta intima-media thickness and sVE serum level, and decreased VE-cad expression in the endothelium of mice. In ApoE-/- mice, IH increased atherosclerotic plaques formation. These effects were blocked by inhibitors of VE-cad cleavage signaling pathway (Fig. 1). We suggest that IH increases endothelial permeability by inducing VE-cad cleavage via the HIF-1 and tyr-kinase pathways, and possibly involving MMP2, PCSK9 and/or ADAM10 proteases. Blocking VE-cad cleavage prevents vascular remodeling and atherosclerotic plaques formation which suggests that VE-cad could be a potential target to a new anti-atherogenesis strategy.