Endothelial BK Channels and Vasoreactivity Following Chronic Hypoxia

慢性缺氧后内皮 BK 通道和血管反应性

基本信息

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
项目类别：
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

项目摘要

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）是由慢性阻塞性肺病（COPD）等肺部疾病和居住在高海拔地区引起的。 CH 在心血管系统内引起多种反应。与长期低氧血症与高血压相关的肺血管系统相反，体循环表现出血管收缩反应性持续普遍降低。后一种现象解释了患有低氧血症的患者表现出显着的全身血管舒张，这可能损害血压的急性调节的观察结果。目前的提案将研究以下假设：CH 后血管反应性的改变是由于血红素加氧酶的内皮活性增强，从而导致一氧化碳 (CO) 的产生增加。 CO 反过来又激活内皮 BK 通道，引起超极化，从而导致血管舒张。我们还将检验以下假设：血红素加氧酶和内皮 BK 通道的活性在 CH 后通过与支架蛋白 Caveolin-1 解离而增强。该项目有三个假设驱动的目标：1) 测试内皮 BK 通道的活性促进慢性缺氧后血管舒张的假设。为此目的提出的实验将检查内皮 BK 通道在血管舒张反应和抵消 CH 大鼠动脉血管收缩中的功能作用。这一目标的完成将确定内皮 BK 通道在先前观察到的 CH 促进血管舒张的作用中的作用。 2) 测试以下假设：慢性缺氧后，内皮细胞 BK 通道活性通过通道与 Caveolin-1 解离而增强。最近的数据表明，内皮 BK 通道与 Caveolin-1 相关，后者可限制其活性。该目的的实验将检查完整动脉中内皮 BK 通道与 Caveolin-1 的关联对通道活性的重要性，并确定 CH 是否影响这种关系。这一目标的完成将为内皮 BK 通道与 Caveolin-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提供新的信息。 3) 检验内皮 HO 和 BK 通道在 CH 后功能耦合的假设。该目标将确定 CH 后内皮 HO 活性是否通过与 Caveolin-1 解离而增加，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元。这一目标的完成将确立 CH 后血管调节的新模式的存在。总之，拟议的研究将为解释先前观察到的 CH 减少血管收缩反应性的作用提供机制见解。这些实验还将产生有关涉及内皮 HO 和 BK 通道的局部血管调节潜在新机制的重要信息。尽管目前的设计研究了 CH 在揭示该通路中的作用，但这些结果很可能在未来扩展到内皮细胞小窝受到类似影响的其他病理生理条件。公共健康相关性：该项目研究了模拟肺部疾病（如慢性阻塞性肺病、慢性支气管炎）以及居住在氧合受损的高海拔地区的模型中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影响。该研究项目探索了一种新的理论来解释这种现象。