Endothelin 1-dependent neurovascular dysfunction in chronic intermittent hypoxia.
Endothelin 1-dependent neurovascular dysfunction in chronic intermittent hypoxia.
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DOI：
10.1161/hypertensionaha.112.193672
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发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
Iadecola C
中科院分区：
文献类型：
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作者：
Capone C;Faraco G;Coleman C;Young CN;Pickel VM;Anrather J;Davisson RL;Iadecola C
阻塞性睡眠呼吸暂停是一种导致慢性间歇性缺氧（CIH）的疾病，是中风和痴呆的独立危险因素，但其作用机制尚不清楚。我们检验了CIH通过改变调节脑血流量的关键机制从而降低脑血管储备而增加脑血管风险的假设。雄性C57Bl6/J小鼠接受CIH （10% O2持续90秒/室内空气持续90秒；在睡眠时间）或假治疗35天。用激光多普勒血流仪对装有颅窗的麻醉小鼠体感觉皮层血流进行评估。CIH增加平均动脉压（从74±2 mm Hg增加到83±3 mm Hg， P<0.05），并减弱神经活动（须刺激；- 39±2%，P<0.05）或新皮质应用内皮依赖性血管扩张剂（乙酰胆碱反应：- 41±3%，P<0.05）产生的血流量增加。脑血管功能障碍与脑小动脉氧化应激有关，可通过清除自由基或抑制NADPH氧化酶来消除。此外，在缺乏NADPH氧化酶NOX2亚基的小鼠中，没有观察到脑血管功能障碍和自由基增加。CIH可显著增加脑血管内皮素1，内皮素A受体拮抗剂BQ123可消除脑血管功能障碍和氧化应激。这些数据首次表明，CIH通过内皮素1和NADPH氧化酶衍生的自由基改变了脑循环的关键调节机制。随之而来的脑血管功能障碍可能通过减少脑血管储备和增加大脑对脑缺血的易感性而增加睡眠呼吸暂停患者中风的风险。
Obstructive sleep apnea, a condition resulting in chronic intermittent hypoxia (CIH), is an independent risk factor for stroke and dementia, but the mechanisms of the effect are unknown. We tested the hypothesis that CIH increases cerebrovascular risk by altering critical mechanisms regulating cerebral blood flow thereby lowering cerebrovascular reserves. Male C57Bl6/J mice were subjected to CIH (10% O2 for 90 seconds/room air for 90 seconds; during sleep hours) or sham treatment for 35 days. Somatosensory cortex blood flow was assessed by laser Doppler flowmetry in anesthetized mice equipped with a cranial window. CIH increased mean arterial pressure (from 74±2 to 83±3 mm Hg; P<0.05) and attenuated the blood flow increase produced by neural activity (whisker stimulation; −39±2%; P<0.05) or neocortical application of endothelium-dependent vasodilators (acetylcholine response: −41±3%; P<0.05). The cerebrovascular dysfunction was associated with oxidative stress in cerebral resistance arterioles and was abrogated by free radical scavenging or NADPH oxidase inhibition. Furthermore, cerebrovascular dysfunction and free radical increase were not observed in mice lacking the NOX2 subunit of NADPH oxidase. CIH markedly increased endothelin 1 in cerebral blood vessels, whereas cerebrovascular dysfunction and oxidative stress were abrogated by neocortical application of the endothelin type A receptor antagonist BQ123. These data demonstrate for the first time that CIH alters key regulatory mechanisms of the cerebral circulation through endothelin 1 and NADPH oxidase– derived radicals. The ensuing cerebrovascular dysfunction may increase stroke risk in patients with sleep apnea by reducing cerebrovascular reserves and increasing the brain’s susceptibility to cerebral ischemia.