Intermittent Hypoxia Impairs Endothelial Function in Early Preatherosclerosis

Abstract

Intermittent hypoxia seems to be a major pathomechanism of obstructive sleep apnea-associated progression of atherosclerosis. The goal of the present study was to assess the influence of hypoxia on endothelial function depending on the initial stage of vasculopathy. We used 16 ApoE-/- mice were exposed to a 6-week-intermittent hypoxia either immediately (early preatherosclerosis) or after 5 weeks of high-cholesterol diet (advanced preatherosclerosis). Another 16 ApoE-/- mice under normoxia served as corresponding controls. Endothelial function was measured by an organ bath technique. Blood plasma CD31+/annexin V+ endothelial microparticles as well as sca1/flk1+ endothelial progenitor cells in blood and bone marrow were analyzed by flow cytometry. The findings were that intermittent hypoxia impaired endothelial function (56.6±6.2% of maximal phenylephrine-induced vasoconstriction vs. 35.2±4.1% in control) and integrity (increased percentage of endothelial microparticles: 0.28±0.05% vs. 0.15±0.02% in control) in early preatherosclerosis. Peripheral repair capacity expressed as the number of endothelial progenitor cells in blood was attenuated under hypoxia (2.0±0.5% vs. 5.3±1.9% in control), despite the elevated number of these cells in the bone marrow (2.0±0.4% vs. 1.1±0.2% in control). In contrast, endothelial function, as well as microparticle and endothelial progenitor cell levels were similar under hypoxia vs. control in advanced preatherosclerosis. We conclude that hypoxia aggravates endothelial dysfunction and destruction in early preatherosclerosis.

Effect on Intermittent Hypoxia on Plasma Exosomal Micro RNA Signature and Endothelial Function in Healthy Adults

“…The presence of altered concentrations, cell sources, and intrinsic properties of circulating microvesicles have been previously noted by several investigators in the context of OSA, whereby the ability of these microvesicles to induce coagulation, angiogenesis, and cell adhesion was noted, and globally believed to reflect a proatherogenic state. 9,[42][43][44][45] The enhanced pro-atherogenic state of OSA is further exemplified by not only the high cardiovascular morbidity burden of this condition, 46 but also by the elevated prevalence of peripheral vascular disease in OSA patients, 47 and multiple investigators have explored the vascular consequences of OSA in different settings. [48][49][50] Our study relied on healthy young adults subjected to a relatively brief IH exposure, such that we can only infer that more chronic exposures to IH in the context of OSA may further exacerbate the pathological changes induced by the disease, and hypothesize that the exosome-related activity on the endothelium will contribute to such processes, as illustrated by the current in vitro experiments.…”

Models of intermittent hypoxia and obstructive sleep apnea: molecular pathways and their contribution to cancer

“…MODELS OF INTERMITTENT HYPOXIA AND OBSTRUCTIVE SLEEP APNEA OSA, intermittent hypoxia can weaken the endothelial wall (149), creating gaps where tumor cells may escape more easily into the blood stream. A study using lung microvascular endothelial cells found that intermittent hypoxia led to reorganization of cytoskeleton and junction proteins causing endothelial barrier dysfunction (88).…”

Endothelial Extracellular Vesicles—Promises and Challenges

“…In addition to pro-inflammatory agents, hypoxia has also been shown to alter the release of MPs from ECs, with highly controversial effects being reported (Vince et al, 2009; Ayers et al, 2014; Lichtenauer et al, 2015; Tuleta et al, 2015; Pichler Hefti et al, 2016). On the one hand, Lichtenauer et al and Vince et al found elevated levels of circulating AnnexinV + /CD31 + and CD106 + EMPs, respectively, in patients after exposure to temporary hypoxic conditions (Vince et al, 2009; Lichtenauer et al, 2015).…”

“…While these groups investigated the effects in healthy volunteers, Tuleta et al assessed the effects of intermittent hypoxia in initial and advanced stages of vasculopathy in mice. Since elevated levels of AnnexinV + /CD31 + EMPs after hypoxic exposure were solely found during early but not advanced stages of vasculopathy, hypoxia might only impair endothelial dysfunction at early stages of vascular diseases but does worsen already advanced stages any further (Tuleta et al, 2015). …”