Effects of obstructive sleep apnea on cerebral circulation

阻塞性睡眠呼吸暂停对脑循环的影响

• 批准号: 8400742
• 负责人: ROBERT M BRYAN
• 金额: $ 34.23万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8400742
• 关键词: Adult; Affect; Aging; Arteries; Attenuated; Biological Availability; Breathing; Cardiovascular Diseases; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Dementia; Elderly; Endothelin; Endothelin Receptor; Endothelin-1; Endothelium; Event; Functional disorder; Generations; Goals; Homeostasis; Human; Hypercapnia; Incidence; Laser-Doppler Flowmetry; Measurement; Mediating; Modeling; Obesity; Obstructive Sleep Apnea; Oxidative Stress; Pathway interactions; Phenotype; Population; Rattus; Reactive Oxygen Species; Regulation; Risk; Risk Factors; Severities; Site; Sleep; Smooth Muscle; Stroke; System; Techniques; Testing; United States; Vascular Smooth Muscle; Vibrissae; arteriole; cerebral artery; cerebral atrophy; cerebrovascular; effective therapy; in vivo; novel; response; soft tissue

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. PUBLIC HEALTH RELEVANCE: Obstructive sleep apnea is defined by interrupted breathing during sleep due to a collapse of the soft tissues in the upper airway. Although obstructive sleep apnea has strong associations to cerebrovascular diseases including stroke and dementia, mechanisms that underlie the effects of obstructive sleep apnea on endothelium and smooth muscle, the sites for cerebral blood flow control, are unknown. The purpose of this proposal is to initiate studies required for understanding the pathological mechanisms associated with cerebrovascular dysfunction following obstructive sleep apnea.

描述（由申请人提供）：阻塞性睡眠呼吸暂停（OSA）的定义是睡眠期间由于上气道软组织塌陷导致呼吸中断。它影响高达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。虽然OSA与脑血管疾病（包括中风和痴呆）有很强的相关性，但OSA对内皮和平滑肌（脑血流（CBF）控制部位）影响的机制尚不清楚。该提案的目的是启动研究，了解与OSA后脑血管功能障碍相关的病理机制。这些研究的一个独特方面涉及我们的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活动的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OSA，因为它发生在人类中，并将有助于提供更完整的理解与OSA在脑循环中的病理事件。我们认为，活性氧和内皮素在一个病理循环中起作用，在脑动脉和小动脉中产生高收缩表型。也就是说，在OSA期间，ROS的产生上调内皮素途径，并且内皮素途径产生ROS。此外，我们提出，通过清除ROS或抑制内皮素通路来打破这种病理循环将抑制脑血管中的病理改变。我们将测试以下假设：在阻塞性睡眠呼吸暂停（OSA）期间，活性氧生成和内皮素之间的循环在脑血管壁中产生病理性改变并扰乱脑血流。我们将在三个具体目标中检验我们的假设。(SA1)确定通过减少ROS来打破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中的脑血管功能障碍。(SA2)确定通过阻断内皮素受体来打破ROS和ET-1之间的循环是否会减轻OSA大鼠28天后动脉和小动脉中的脑血管功能障碍。(SA3)确定28天的OSA是否降低CBF，减弱CBF对触须刺激的反应，减弱自动调节或减弱CBF对高碳酸血症的反应。确定是否减少ROS和/或阻断内皮素受体恢复这些反应在体内。我们将使用离体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CBF来完成这些特定目标。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，并采取更有效的治疗方法来减少OSA对脑循环的破坏性影响，以降低中风的发生率和痴呆的严重程度。 公共卫生相关性：阻塞性睡眠呼吸暂停是指由于上呼吸道软组织的塌陷而导致的睡眠期间呼吸中断。虽然阻塞性睡眠呼吸暂停与脑血管疾病（包括中风和痴呆）有很强的相关性，但阻塞性睡眠呼吸暂停对脑血流控制部位内皮和平滑肌影响的机制尚不清楚。本提案的目的是启动研究，了解阻塞性睡眠呼吸暂停后脑血管功能障碍的病理机制。