CHRONIC INTERMITTENT HYPOXIA, NEUROVASCULAR DYSFUNCTION AND STROKE

描述（由申请人提供）：睡眠呼吸障碍，包括睡眠呼吸暂停（SA），其特征是睡眠期间周期性呼吸中断，通常由间歇性气道阻塞引起。SA正在成为死亡和残疾的一个非常普遍的原因。除高血压和心脏病外，SA是脑卒中的独立危险因素，其发病率增加2-4倍。由于缺乏对SA如何增加脑血管功能不全和卒中风险的深入了解，基于机制的治疗的发展受到阻碍。虽然SA的病理生理可能是多因素的，但由呼吸暂停发作引起的慢性间歇性缺氧（CIH）被认为是心血管并发症的关键因素。在体循环中，CIH，像SA一样，改变血管功能，但很少有人知道这些改变对器官血流调节和终末器官损伤的影响，特别是在大脑中。考虑到大脑对血管功能不全的独特易感性，CIH对大脑血液供应的调节的破坏可能会损害向组织输送足够的血流量并促进缺血性损伤。目前的建议将测试的中心假设，CIH发挥其有害的影响，通过改变关键的脑血管稳态机制，减少血管储备和增加大脑缺血的脆弱性的大脑。特别是，我们将从四个方面来检验以下具体假设：（1）CIH通过改变保证足够脑灌注的重要调节机制，如功能性充血和脑血管自动调节，来破坏向脑的血液输送;（2）CIH通过产生超氧化物的酶NADPH氧化酶诱导血管氧化应激来发挥其有害的脑血管效应;（3）脑血管内皮素-1（ET-1）通过ETA受体表达上调，在神经血管功能障碍中起重要作用;（4）CIH的脑血管效应消耗脑血管储备，加重大脑中动脉闭塞引起的脑缺血，加重组织损伤。这些假设将使用CIH小鼠模型和完善的方法来检验脑血管调节和缺血性脑损伤。拟议的研究结果将提供新的见解，可能会推进我们的理解SA的脑血管并发症。

DESCRIPTION (provided by applicant): Sleep-disordered breathing, including sleep apnea (SA), is characterized by cyclical interruption of breathing during sleep, often caused by intermittent airway obstruction. SA is emerging as a highly prevalent cause of death and disability. In addition to hypertension and cardiac diseases, SA is an independent risk factor for stroke, and increases its incidence by 2-4 folds. The development of mechanism-based therapies has been hampered by the lack of insight into how SA increases the risk of cerebrovascular insufficiency and stroke. Although the pathophysiology of SA is likely to be multifactorial, chronic intermittent hypoxia (CIH) caused by the apneic episodes is considered a critical factor in the cardiovascular complications. In the systemic circulation, CIH, like SA, alters vascular function, but little is known about the impact of these alterations on the regulation of organ blood flow and on end-organ damage, particularly in brain. Considering the brain's unique susceptibility to vascular insufficiency, disruption of the regulation of the cerebral blood supply by CIH could compromise the delivery of adequate blood flow to the tissue and promote ischemic injury. The present proposal will test the central hypothesis that CIH exerts its deleterious effect on the brain by altering key cerebrovascular homeostatic mechanisms, reducing vascular reserves and increasing the vulnerability of the brain to ischemia. In particular, we will test the following specific hypotheses in four aims: (1) CIH disrupts the delivery of blood to the brain by altering vital regulatory mechanisms that assure adequate cerebral perfusion, such as functional hyperemia and cerebrovascular autoregulation; (2) CIH exerts its deleterious cerebrovascular effects by inducing vascular oxidative stress through the superoxide producing enzyme NADPH oxidase; (3) Upregulation of endothelin-1 in cerebral blood vessels, via ETA receptors, plays a major role in the neurovascular dysfunction; (4) The detrimental cerebrovascular effects of CIH deplete cerebrovascular reserves, aggravate the brain ischemia induced by middle cerebral artery occlusion, and increase the resulting tissue damage. These hypotheses will be tested using a mouse model of CIH and well-established approaches to examine cerebrovascular regulation and ischemic brain injury. The results of the proposed studies will provide new insights that may advance our understanding of the cerebrovascular complications of SA.