Endothelial nitric oxide synthase uncoupling: a novel pathway in OSA induced vascular endothelial dysfunction

Respir Physiol Neurobiol. 2015 Feb 1:207:40-7. doi: 10.1016/j.resp.2014.12.012. Epub 2014 Dec 19.


The mechanism of vascular endothelial dysfunction (VED) and cardiovascular disease in obstructive sleep apnea (OSA) is unknown. We performed a comprehensive evaluation of endothelial nitric oxide synthase (eNOS) function directly in the microcirculatory endothelial tissue of OSA patients who have very low cardiovascular risk status. Nineteen OSA patients underwent gluteal biopsies before, and after effective treatment of OSA. We measured superoxide (O2(•-)) and nitric oxide (NO) in the microcirculatory endothelium using confocal microscopy. We evaluated the effect of the NOS inhibitor l-Nitroarginine-Methyl-Ester (l-NAME) and the NOS cofactor tetrahydrobiopterin (BH4) on endothelial O2(•-) and NO in patient endothelial tissue before and after treatment. We found that eNOS is dysfunctional in OSA patients pre-treatment, and is a source of endothelial O2(•-) overproduction. eNOS dysfunction was reversible with the addition of BH4. These findings provide a new mechanism of endothelial dysfunction in OSA patients and a potentially targetable pathway for treatment of cardiovascular risk in OSA.

Keywords: Endothelial dysfunction; Hypertension; Nitric oxide; Obstructive sleep apnea.

MeSH terms

  • Adult
  • Biopterins / analogs & derivatives
  • Biopterins / pharmacology
  • Cardiovascular Diseases / etiology*
  • Continuous Positive Airway Pressure / methods
  • Endothelium / drug effects
  • Endothelium / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Male
  • Middle Aged
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide Synthase Type III / metabolism*
  • Sleep Apnea, Obstructive / complications*
  • Sleep Apnea, Obstructive / pathology*
  • Sleep Apnea, Obstructive / therapy


  • Enzyme Inhibitors
  • Biopterins
  • Nitric Oxide Synthase Type III
  • sapropterin
  • NG-Nitroarginine Methyl Ester