Complement promotes endothelial von Willebrand factor and angiopoietin-2 release in obstructive sleep apnea

Abstract

Study Objective Obstructive sleep apnea (OSA) is highly prevalent and triples vascular thromboembolic risk. Intermittent hypoxia (IH) during transient cessation of breathing in OSA impairs endothelial protection against complement. Complement activation stimulates the endothelial release of a pro-thrombotic von Willebrand factor (vWF). We investigated whether increased complement activity in OSA promotes the endothelial release of vWF and pro-inflammatory angiopoietin-2. We further investigated whether improving complement protection with statins reverses these changes. Methods Using endothelial cells (ECs) and blood collected from OSA patients (n = 109) and controls (n = 67), we assessed whether altered cellular localization of complement inhibitor CD59 in OSA modulates exocytosis of Weibel-Palade bodies (WPB), secretory granules that store vWF and angiopoietin-2. These interactions were also assessed in vitro in ECs exposed to normoxia or IH with or without recombinant complement C9 and with or without atorvastatin. Results Circulating levels of angiopoietin-2 were greater in OSA than controls and levels of vWF cleavage products correlated with OSA severity. In cultured ECs, IH enhanced complement-stimulated angiopoietin-2 and vWF release by reducing EC surface and increasing intracellular expression of complement inhibitor CD59. Intracellular CD59 co-localized with WPB in OSA. IH increased binding of intracellular CD59 to syntaxin-3, which dissociated syntaxin-3 from voltage-sensitive calcium channel Cav1.2, and activated WPB exocytosis in a calcium-dependent manner. Atorvastatin reversed IH-enhanced endothelial release of vWF and angiopoietin-2. Conclusions IH promotes the complement-mediated release of vWF and angiopoietin-2, which may contribute to pro-thrombotic and pro-inflammatory conditions in OSA. Statin reversed these effects, suggesting a potential approach to reduce cardiovascular risk in OSA.

Evoked Weibel‐Palade Body Exocytosis Modifies the Endothelial Cell Surface by Releasing a Substrate‐Selective Phosphodiesterase

“…[ 38 , 44 , 45 ] A recent study in HUVEC could show that in intermittent hypoxia conditions, CD59 plasma membrane presentation is impaired and consequently ECs are more accessible to complement attack and MAC deposition. [ 46 ] Interestingly, MAC assembly on nucleated cells has been shown to be largely non‐cytolytic and on endothelial cells, it can trigger NLRP3 inflammasome formation and the release of pro‐inflammatory cytokines such as IL‐1β which promote leukocyte adhesion. [ 38 , 47 ] This pro‐inflammatory activity could be the result of only transient membrane pores formed by the MAC that permit K + efflux and Ca 2+ influx but are then efficiently removed by endocytosis and/or exocytotic membrane shedding.…”

May continuous positive airway pressure (CPAP) treatment be detrimental in obstructive sleep apnea?

“…These results confirm previous results from the same group showing increased circulating levels of Ang-2 in OSA patients compared to controls. 5 Moreover, elevated Ang-2 levels were found in patients with moderate-severe OSA after 3–6 months of CPAP treatment. 6 A clinically important finding was that statin treatment blunted the increase in the levels of markers of endothelial damage in CPAP-treated OSA patients.…”