Mechanisms of Metabolic Vasodilation

代谢性血管舒张机制

• 批准号: 6865427
• 负责人: INGRID H SARELIUS
• 金额: $ 35.12万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-05 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6865427
• 关键词: adenosine; arterioles; biological signal transduction; confocal scanning microscopy; exercise; genetically modified animals; hemodynamics; laboratory mouse; metabolism; microcirculation; muscle contraction; nitric oxide; potassium channel; striated muscles; thapsigargin; vascular endothelium; vasodilation; video microscopy

Regulation of blood flow and metabolic rate are closely coupled in striated muscle, but the pathways that specifically enable vasoactive metabolites to produce integrated arteriolar responses remain elusive. We have identified endothelial cells (EC), and EC Ca 2+ changes, as essential for metabolic vasodilation in resistance arterioles. This dilation involves, KATP channels, nitric oxide and adenosine, but how KATP channel activity relates to the actions of NO and adenosine is not clear. Importantly, the contribution of NO to this dilation is most prominent in ischemic conditions, i.e. mechanisms of metabolic vasodilation are modified by flow. The studies will use cremaster muscle of anesthetised mice to determine the mechanisms of this response in free flow and ischemic conditions. Intravital confocal microscopy will be used to quantify EC Ca 2+ and arteriolar diameter changes during skeletal muscle contraction. We will test 3 hypotheses that are based on our preliminary findings. Hyp. I: In metabofic vasodilation, KATP channels are required for the production of EC Ca 2+ changes. Hyp. Il: EC Ca 2+ changes are essential for metabolic vasodilation in all flow conditions. These changes consist of two components - an early increase mobilised from intracellular stores, and an oscillatory component dependent on extracellular calcium sources. Hyp. IIl: (Part A) NO of endothelial origin contributes significantly to the metabolic vasodilation that occurs during ischemic conditions, but is a much less important component of the response during free flow. (Part B) NO from non-endothelially located nNOS also contributes to metabofic vasodilation (particularly during ischemia) both by a direct effect on SMCs and by stimulating release of NO from endothelial cells. The studies will contribute to the general understanding of how local responses to physiological signals are integrated in blood vessel walls, and will contribute significantly to the broad goal of understanding the metabolic response to exercise. A full understanding of the mechanisms underlying exercise is relevant to many areas of human health.

在横纹肌中，血流和代谢率的调节是紧密耦合的，但是使血管活性代谢物产生综合小动脉反应的途径仍然是难以捉摸的。 我们已经确定了内皮细胞（EC）和EC Ca 2+的变化是阻力小动脉代谢性血管舒张的必要条件。 这种扩张涉及KATP通道、一氧化氮和腺苷，但KATP通道活性如何与NO和腺苷的作用相关尚不清楚。 重要的是，NO对这种扩张的贡献在缺血性疾病中最为突出，即代谢性血管扩张的机制被流动改变。 这些研究将使用麻醉小鼠的提睾肌来确定这种反应在自由流动和缺血条件下的机制。 活体共聚焦显微镜将用于定量骨骼肌收缩过程中EC Ca 2+和小动脉直径的变化。 我们将测试基于我们初步发现的三个假设。 嗨 I：在代谢性血管舒张中，KATP通道是产生EC Ca 2+变化所必需的. 嗨 在所有血流条件下，IL：ECCa 2+的变化对代谢性血管舒张是必不可少的. 这些变化包括两个组成部分-早期增加动员从细胞内商店，和振荡组件依赖于细胞外钙源。 嗨 III：（A部分）内皮来源的NO显著促进在缺血条件期间发生的代谢性血管舒张，但在自由流动期间是反应的不太重要的组分。 (Part B）来自非内皮定位的nNOS的NO也通过对SMC的直接作用和通过刺激NO从内皮细胞的释放而有助于代谢性血管舒张（特别是在局部缺血期间）。 这些研究将有助于对生理信号的局部反应如何整合在血管壁中的一般理解，并将显著有助于理解运动代谢反应的广泛目标。 充分了解运动的基本机制与人类健康的许多领域有关。