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

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 USA. We measured superoxide (O-2(center dot-)) 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 O-2(center dot-) and NO in patient endothelial tissue before and after treatment. We found that eNOS is dysfunctional in USA patients pre-treatment, and is a source of endothelial O-2(center dot-) overproduction. eNOS dysfunction was reversible with the addition of BH4. These findings provide a new mechanism of endothelial dysfunction in USA patients and a potentially targetable pathway for treatment of cardiovascular risk in USA. (C) 2015 Elsevier B.V. All rights reserved.