Endothelial BK Channels and Vasoreactivity Following Chronic Hypoxia

慢性缺氧后内皮 BK 通道和血管反应性

• 批准号: 7983105
• 负责人: BENJIMEN R WALKER
• 金额: $ 37.63万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7983105
• 关键词: Accounting; Acids; Acute; Affect; Agonist; Altitude; Animal Experiments; Animals; Arteries; Blood Circulation; Blood Pressure; Blood Vessels; Calcium; Carbon Monoxide; Cardiovascular system; Caveolae; Cell membrane; Cells; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Coupled; Cytochrome P450; Data; Disease; Dissociation; Electrophysiology (science); Endothelial Cells; Endothelium; Enzyme Inhibition; Event; Excision; Future; Goals; Heme; Hypertension; Hypoxemia; Hypoxia; Image; Knowledge; Laboratories; Lung; Lung diseases; Maintenance; Measures; Membrane Potentials; Modeling; Muscle relaxation phase; Nitric Oxide; Oxygen; Oxygenases; Pathway interactions; Patient observation; Peptides; Physiological; Play; Potassium; Production; Qualifying; Rattus; Reflex action; Regulation; Research; Research Project Grants; Resistance; Role; Ryanodine; Scaffolding Protein; Signal Pathway; Smooth Muscle; Smooth Muscle Myocytes; Stimulus; System; Testing; Therapeutic; Tissues; Vascular Smooth Muscle; Vasoconstrictor Agents; Vasodilation; Work; autocrine; blood pressure regulation; caveolin 1; design; enzyme activity; insight; large-conductance calcium-activated potassium channels; novel; public health relevance; research study; residence; response; scaffold; theories; vasoconstriction

DESCRIPTION (provided by applicant): Chronic hypoxia (CH) results from pulmonary disorders such as COPD and from residence at high altitude. CH elicits a variety of responses within the cardiovascular system. In contrast to the pulmonary vasculature where long-term hypoxemia is associated with hypertension, the systemic circulation demonstrates a persistent generalized reduction in vasoconstrictor reactivity. This latter phenomenon accounts for the observation that patients suffering from hypoxemic disorders display significant systemic vasodilation that may impair acute regulation of blood pressure. The present proposal will investigate the hypothesis that altered vascular reactivity following CH is due to enhanced endothelial activity of the enzyme heme oxygenase with resultant increased production of carbon monoxide (CO). CO, in turn, activates endothelial BK channels to cause hyperpolarization leading to vasodilation. We also will test the hypothesis that the activities of heme oxygenase and endothelial BK channels are enhanced following CH by their dissociation from the scaffolding protein caveolin-1. There are three hypothesis-driven aims for the project: 1) Test the hypothesis that activity of endothelial BK channels promotes vasodilation following chronic hypoxia. Experiments proposed in this aim will examine the functional role of endothelial BK channels in both vasodilatory responses and in offsetting vasoconstriction in arteries from CH rats. Completion of this aim will establish a role of endothelial BK channels in the previously observed effect of CH to promote vasodilation. 2) Test the hypothesis that endothelial cell BK channel activity is enhanced following chronic hypoxia by dissociation of the channel from caveolin-1. Recent data suggest that endothelial BK channels are associated with caveolin-1 which acts to limit their activity. Experiments in this aim will examine the significance of association of endothelial BK channels with caveolin-1 in intact arteries on channel activity and determine if CH affects this relationship. Completion of this aim will provide novel information on how the association of endothelial BK channels with caveolin-1 affects vasoreactivity and how hypoxia alters this interaction. 3) Test the hypothesis that endothelial HO and BK channels are functionally coupled following CH. This aim will determine if endothelial HO activity is increased following CH by dissociation from caveolin-1 and if HO and BK channels act as a regulatory unit controlling endothelial cell membrane potential and vascular reactivity. Completion of this aim will establish the presence of a novel mode of vascular regulation present following CH. Together, the proposed studies will provide mechanistic insight to explain the previously observed effect of CH to diminish vasoconstrictor reactivity. These experiments will also generate important information on a potentially novel mechanism of local vascular regulation involving endothelial HO and BK channels. Although the current design investigates the role of CH to unmask this pathway, it is likely that these results could be extended in the future to other pathophysiological conditions where endothelial caveolae are similarly affected. PUBLIC HEALTH RELEVANCE: This project investigates the mechanisms that account for altered control of blood pressure in a model that mimics pulmonary diseases such as chronic obstructive pulmonary disease, chronic bronchitis as well as residence at high altitude where oxygenation is impaired. In these settings, maintenance of blood pressure may be compromised. This research project explores a novel theory to explain this phenomenon.

描述（由申请人提供）：慢性缺氧（CH）是由COPD等肺部疾病和高海拔地区的住所的结果。 CH引起心血管系统中的各种反应。与长期缺氧与高血压相关的肺脉管系统相反，全身循环表明血管收缩反应性的持续概括。后一种现象解释了这样一种观察结果，即患有缺氧性疾病的患者显示出明显的全身性血管舒张，可能会损害血压的急性调节。本提案将调查CH后血管反应性改变的假设是由于酶血红素氧酶的内皮活性增强，导致一氧化碳（CO）的产生增加。 CO反过来激活内皮BK通道以引起超极化导致血管舒张。我们还将检验以下假设：在CH之后，血红素加氧酶和内皮BK通道的活性通过与脚手架蛋白小窝蛋白1的解离后增强了CH。该项目有三个假设驱动的目的：1）检验以下假设：内皮BK通道的活性促进了慢性缺氧后血管舒张。此目标中提出的实验将检查内皮BK通道在血管舒张反应中的功能作用，并在抵消CH大鼠动脉的血管收缩中。该目标的完成将确立内皮BK通道在先前观察到的CH促进血管舒张作用中的作用。 2）检验假设，即通过与小窝蛋白-1的通道解离慢性缺氧后内皮细胞BK通道活性得到了增强。最近的数据表明，内皮BK通道与Caveolin-1有关，该通道起来限制其活性。此目标中的实验将检查内皮BK通道与可爱素-1在完整动脉中对通道活性的关联的重要性，并确定CH是否影响这种关系。此目标的完成将提供有关内皮BK通道与小窝蛋白-1的关联如何影响血管反应性以及缺氧如何改变这种相互作用的新信息。 3）检验了CH后内皮HO和BK通道在功能上耦合的假设。该目标将确定通过从小窝蛋白-1解离CH后，内皮HO活性是否增加，以及HO和BK通道是否充当控制内皮细胞膜电位和血管反应性的调节单位。此目标的完成将确定CH后存在的新型血管调节模式。 共同的研究将提供机械洞察力，以解释CH对血管收缩反应性降低的先前观察到的影响。这些实验还将生成有关涉及内皮HO和BK通道的局部血管调节机制的潜在新机制的重要信息。尽管当前的设计研究了CH揭示这一途径的作用，但将来可能会扩展这些结果到其他病理生理状况，而这些病理生理条件类似地受到影响。 公共卫生相关性：该项目研究了模仿肺部疾病（例如慢性阻塞性肺部疾病，慢性支气管炎以及在高海拔受损的高海拔）中的肺部疾病模型中对血压控制改变的机制。在这些情况下，血压的维持可能会受到损害。该研究项目探讨了一种新的理论来解释这一现象。