Endothelial glycocalyx perturbation in obstructive sleep apnea is associated with repetitive hypoxemia and immunothrombotic endothelial dysfunction

Müller, Martin Bernhard; Kammerer, Tobias; Khan, Humayun; Schmid, Annika; Hirschberger, Simon; Hübner, Max; Barth, Teresa K.; Mitsigiorgi, Rea; Stihl, Clemens; Holzer, Martin; Jira, Daniel; Patscheider, Martin; Weiss, Bernhard G.; Reichel, Christoph Andreas; Uhl, Bernd (2026): Endothelial glycocalyx perturbation in obstructive sleep apnea is associated with repetitive hypoxemia and immunothrombotic endothelial dysfunction. Journal of Translational Medicine, 24: 777. ISSN 1479-5876

Abstract

Background

Obstructive sleep apnea (OSA) is associated with cardiovascular disease. The endothelial glycocalyx (eGCX) is a shear-sensitive intravascular barrier. The relevance of OSA and intermittent hypoxia (IH) for eGCX perturbation and cardiovascular disease in humans remains unclear.

Methods

In a prospectively recruited observational cohort with cross-sectional biomarker analysis in men ( n = 60), polysomnography quantified apnea-hypopnea index (AHI), oxygen desaturation index (ODI), and hypoxic burden (HB). Using single-time-point plasma sampling, eGCX glycosaminoglycans hyaluronan (HA) and heparan sulfate (HS) and the proteoglycan syndecan-1 (SDC-1) were related to OSA severity and repetitive hypoxemia, including multivariable adjustment for cardiometabolic, inflammatory, and renal determinants. Plasma proteomics defined pathways associated with OSA and HA/HS. Shear-matured primary human endothelial cells were exposed to OSA-characteristic IH cycles under arterial flow to assess eGCX structure, oxidative stress, nitric oxide (NO) signaling, thromboinflammatory status, and antioxidant treatment with N-acetylcysteine.

Results

Plasma HA and HS were higher in OSA than in non-OSA individuals and increased stepwise with disease severity, tracking AHI, ODI, and HB. These associations persisted in multivariable analyses adjusting for age, BMI, hypertension, hs-CRP, fasting glucose, and eGFR. Plasma SDC-1 did not differ between groups and remained non-associated in adjusted analyses. Proteomics revealed enrichment of inflammatory, coagulation, and oxidative stress-related pathways that strengthened with increasing OSA burden and higher HA/HS levels. Experimentally, IH caused loss of endothelial surface HA/HS with increased shedding, increased reactive oxygen species, reduced redox capacity, impaired NOS3/eNOS signaling and reduced NO bioavailability. IH or enzymatic eGCX digestion each enhanced monocyte and platelet adhesion, tissue factor expression, and fibrin deposition under shear, while N-acetylcysteine attenuated oxidative stress and partially restored surface HA expression.

Conclusions

Integrated patient and IH-model data show that OSA severity and repetitive hypoxemia are associated with circulating markers consistent with eGCX perturbation, while the endothelial IH model supports induction of oxidative-inflammatory stress and a proadhesive, prothrombotic phenotype by intermittent hypoxia. Together, circulating HA and HS emerge as candidate biomarkers associated with OSA-related eGCX perturbation, warranting further evaluation in longitudinal and interventional studies of eGCX-stabilizing adjunct therapies. These findings derive from an all-male cohort and require validation in women and more diverse populations.

• Dokumententyp: Artikel (Klinikum der LMU)
• Organisationseinheit (Fakultäten): 07 Medizin > Klinikum der LMU München > Klinik für Anaesthesiologie; 07 Medizin > Klinikum der LMU München > Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde
• DFG-Fachsystematik der Wissenschaftsbereiche: Lebenswissenschaften
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 413635475
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892