Abstract 106: Chronic Intermittent Hypoxia Induces Neurovascular Dysfunction through Endothelin-1 and Nox2-Derived Radical
Obstructive sleep apnea (OSA), a condition resulting in chronic intermittent hypoxia (CIH), is an independent risk factor for ischemic stroke, but the mechanisms of the effect are unknown. We hypothesized that CIH increases stroke risk by altering the regulation of cerebral blood flow (CBF) and increasing the brain’s susceptibility to ischemia. Male C57Bl/6 mice (n=5/group) were subjected to CIH (10% O2 for 90 sec/room air for 90 sec; during sleep hours) for 14 or 35 days (d). Sham-treated mice received room air according to the same schedule. Somatosensory cortex CBF was assessed by laser-Doppler flowmetry in anesthetized mice equipped with a cranial window. CIH increased mean arterial pressure only at 35d (from 74±2 to 83±3 mmHg (p<0.05). However, CIH attenuated the CBF increase produced by neocortical application of the endothelium-dependent vasodilator acetylcholine (sham: 22±1%; CIH:13±1%;p<0.05) and by whisker stimulation (sham: 23±1%;CIH: 14±1%;p<0.05) both at 14 and 35d. CIH did not alter the CBF increase evoked by adenosine (sham: 23±3%; CIH: 25±1%; p>0.05), indicating that smooth muscle relaxation was not compromised. The effects of CIH were prevented by neocortical application of the endothelin (ET) type A (ETA) receptor antagonist BQ123 (1µM;p<0.05) and were associated with ET1 up-regulation in cerebral blood vessels (sham: 52±26;CIH: 5,486±2,466 pg/mg;p<0.05;by ELISA). The angiotensin-II AT1 receptor inhibitor losartan (5µM) did not affect the dysfunction (p>0.05). CIH increased reactive oxygen species (ROS) by 2.3±0.5 folds (p<0.05), assessed by hydroethidine, an effect blocked by the ROS scavenger MnTBAP (100µM; p<0.05) or by BQ123 (p<0.05). Furthermore, the cerebrovascular dysfunction was absent in mice lacking the Nox2-/- subunit of the superoxide-producing enzyme NADPH oxidase and was reversed by neocortical application of a NADPH oxidase peptide inhibitor. The data show that CIH, induces profound alterations of key regulatory mechanisms of cerebral circulation through ET1 and Nox2-dependent ROS production, and raises the possibility that cerebrovascular dysfunction may underlie the increased stroke risk in patients with OSA.
- © 2012 by American Heart Association, Inc.