Endothelial Dysfunction and Circulating Microparticles from Patients with Obstructive Sleep Apnea

Endothelial dysfunction is involved in vascular complications of obstructive sleep apnea (OSA). In this study, circulating microparticles (MPs) from patients with OSA-induced nocturnal desaturations were characterized and their effects on endothelial function were evaluated. Two age-matched groups of patients undergoing polysomnography for OSA were compared: 35 desaturators with a 3% oxyhemoglobin desaturation index (ODI) ≥ 10 events per hour of sleep and 27 nondesaturators with ODI <10 events per hour. MPs were characterized by flow cytometry and then either used to treat in vitro human endothelial cells or to study endothelial function in mice. Circulating MPs did not differ between groups, but MPs from granulocytes and activated leukocytes (CD62L⁺) were found at higher levels in desaturators. In vitro, MPs from desaturators reduced endothelial nitric oxide (NO) production by enhancing phosphorylation of endothelial NO synthase at the site of inhibition and expression of caveolin-1. CD62L⁺ MPs positively correlated with ODI. Endothelial NO production negatively correlated with both CD62L⁺ MPs and ODI. MPs from desaturators increased expression of endothelial adhesion molecules including E-selectin, ICAM-1 and ITGA5, and cyclooxygenase 2. Moreover, injection of MPs from desaturators into mice impaired endothelium-dependent relaxation in aorta and flow-induced dilation in small mesenteric arteries. This study demonstrates an association between endothelial dysfunction and increased circulating levels of CD62L⁺ MPs. This may initiate atherogenic processes in patients with OSA and severe nighttime hypoxia.Obstructive sleep apnea (OSA) is a highly prevalent disease characterized by recurrent episodes of partial or complete obstruction of the upper airways during sleep, leading to repeated falls in oxygen saturation. There is growing evidence in support of an independent association between OSA and cardiovascular diseases,¹ particularly for sleep disordered breathing accompanied by marked nocturnal oxygen desaturations.^2,3 Various pathophysiological mechanisms have been proposed to contribute to the pathogenesis of vascular morbidity, including autonomic dysfunction, hypercoagulability, inflammation, oxidative stress, and endothelial dysfunction.⁴ An impairment of endothelial function has been recently demonstrated in patients with OSA and nocturnal desaturations compared with matched OSA patients without desaturations.⁵ Very recently, it was shown that OSA directly affects the vascular endothelium by promoting inflammation and oxidative stress, and decreasing nitric oxide (NO) availability and repair capacity, as shown by reduced circulating levels of endothelial progenitor cells.⁶Microparticles (MPs) are small membrane vesicles that are shed from cells in response to activation and apoptosis. The number, cellular source, and composition of MPs are altered in various disease states including diabetes, metabolic syndrome, sepsis, and pre-eclampsia.^7,8,9,10 Recent data suggested that MPs might play a major role in interactions with circulating cells or the components of the vessel wall. MPs have been implicated in coagulation, inflammation, and vascular function.¹¹ With regard to OSA, Geiser et al¹² did not report an increase of platelet-derived MPs despite enhanced in vivo platelet activation. Recently, Ayers et al¹³ found that procoagulant, platelet-, and leukocyte-derived MPs were significantly increased in patients with OSA with marked nocturnal desaturations (>7.5 oxygen desaturations per hour).To our knowledge, the role of circulating MPs in the regulation of endothelial dysfunction in OSA is unknown. Thus, the aims of this study were to characterize circulating MPs from patients with OSA according to their cellular origins and determine in vitro effects of MPs from OSA patients on endothelial cells with respect to NO and superoxide anion (O₂⁻) productions and the expression of adhesion and proinflammatory molecules involved in inflammation. Finally, MPs were injected into mice intravenously to test their pathophysiological relevance.