Effects of obstructive sleep apnea on cerebral circulation

描述（由申请人提供）：阻塞性睡眠呼吸暂停（OSA）的定义是由于上呼吸道软组织塌陷而导致睡眠期间呼吸中断。它影响了高达25%的成年人口，并且经常被忽视为许多病理状况的潜在原因。尽管OSA与包括中风和痴呆在内的脑血管疾病有很强的相关性，但OSA对内皮细胞和平滑肌（脑血流量控制部位）影响的机制尚不清楚。本提案的目的是开展必要的研究，以了解OSA后脑血管功能障碍的病理机制。这些研究的一个独特之处在于我们的OSA大鼠模型。在这个新开发的模型中，我们将在未麻醉的自由放养大鼠的睡眠周期中阻塞气道。该模型具有几个重要的特征，更接近地模拟了OSA在人类中的发生，将有助于更全面地了解脑循环中与OSA相关的病理事件。我们认为，ROS和内皮素在一个病理循环中作用，在脑动脉和小动脉中产生过度收缩表型。即在OSA期间，ROS的生成上调了内皮素通路，内皮素通路产生ROS。此外，我们提出通过清除ROS或抑制内皮素途径来打破这种病理循环将抑制脑血管的病理改变。我们将验证以下假设：在OSA期间，ROS生成和内皮素之间的循环会在脑血管壁产生病理改变并扰乱脑血流。我们将在三个具体目标中检验我们的假设。（SA1）测定通过降低ROS打破ROS与ET-1之间的循环是否会减轻OSA 28天后大鼠动脉和小动脉的脑血管功能障碍。（SA2）通过阻断内皮素受体打破ROS和ET-1之间的循环是否会减轻OSA 28天后大鼠动脉和小动脉的脑血管功能障碍。（SA3）确定28天的OSA是否降低CBF，减弱CBF对须刺激的反应，减弱自身调节，或减弱CBF对高碳酸血症的反应。确定减少ROS和/或阻断内皮素受体是否能在体内恢复这些反应。我们将使用孤立的加压脑动脉和小动脉，并使用放射自显影技术和激光多普勒血流仪测量脑血流来完成这些特定的目标。这些研究的完成将使我们更好地了解脑血管功能障碍的潜在机制，并寻求更有效的治疗方法，以减少OSA对脑循环的破坏性影响，从而降低中风的发病率和痴呆的严重程度。

DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) is defined by interrupted breathing during sleep due to a collapse of the soft tissues in the upper airway. It affects up to 25% of the adult population and is often overlooked as being an underlying cause for a number of pathological conditions. Although OSA has strong associations to cerebrovascular diseases including stroke and dementia, mechanisms that underlie the effects of OSA on endothelium and smooth muscle, the sites for cerebral blood flow (CBF) control, are unknown. The purpose of this proposal is to initiate studies required for understanding the pathological mechanisms associated with cerebrovascular dysfunction following OSA. One unique aspect of these studies involves our rat model of OSA. In this newly developed model, we will obstruct the airway during the sleep cycle in unanesthetized, freely- ranging rats. This model has several important features that more closely mimics OSA as it occurs in the human and will help to provide a more complete understanding of the pathological events associated with OSA in the cerebral circulation. We propose that ROS and endothelin act in a pathological cycle to produce a hypercontractile phenotype in cerebral arteries and arterioles. That is, during OSA, generation of ROS upregulates the endothelin pathway and the endothelin pathway generates ROS. Further, we propose that breaking this pathological cycle by either scavenging ROS or inhibiting the endothelin pathway will inhibit the pathological alterations in cerebral vessels. We will test the following hypothesis: During OSA a cycle between ROS generation and endothelin produces pathological alterations in the cerebrovascular wall and disrupts cerebral blood flow. We will test our hypothesis in three specific aims. (SA1) Determine if breaking the cycle between ROS and ET-1 by reducing ROS will alleviate the cerebrovascular dysfunction in arteries and arterioles in rats following 28 days of OSA. (SA2) Determine if breaking the cycle between ROS and ET-1 by blocking endothelin receptors will alleviate the cerebrovascular dysfunction in arteries and arterioles in rats following 28 days of OSA. (SA3) Determine if 28 days of OSA decreases CBF, attenuates the CBF response to whisker stimulation, attenuates autoregulation, or attenuates the CBF response to hypercapnia. Determine if reducing ROS and/or blocking endothelin receptors restores these responses in vivo. We will complete these specific aims using isolated pressurized cerebral arteries and arterioles and measurement of CBF with autoradiographic techniques and laser Doppler flowmetry. Completion of these studies will move us toward a better understanding of the underlying mechanisms of cerebrovascular dysfunction and towards more effective treatments to reduce the devastating effects of OSA on the cerebral circulation with a goal of reducing the incidence of stroke and the severity of dementias.