Mechanisms of Metabolic Vasodilation

代谢性血管舒张机制

• 批准号: 6761354
• 负责人: INGRID H SARELIUS
• 金额: $ 36.62万
• 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/6761354
• 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，血流调节和代谢率是紧密耦合的，但使血管活性代谢物产生完整小动脉反应的具体途径仍然难以捉摸。我们发现血管内皮细胞(EC)和内皮细胞钙离子的变化是阻力小动脉代谢血管扩张所必需的。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和腺苷的作用有关尚不清楚。重要的是，NO对这种扩张的贡献在缺血条件下最为突出，即代谢性血管扩张机制被血流改变。这项研究将使用麻醉小鼠的提睾肌来确定在自由流动和缺血条件下这种反应的机制。活体共聚焦显微镜将被用来量化在骨骼肌收缩过程中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3个假设。Hyp.I：在代谢性血管扩张中，KATP通道是产生EC钙变化所必需的。Hyp.IL：在所有血流条件下，内皮细胞钙离子的变化对代谢性血管扩张都是必不可少的。这些变化由两个部分组成--从细胞内储存中动员的早期增加，以及依赖于细胞外钙来源的振荡成分。Hyp.IIL：(A部分)内皮来源的NO在缺血条件下发生的代谢性血管扩张中起重要作用，但在自由血流时的反应中的作用要小得多。(B部分)来自非内皮细胞的NO还通过直接作用于SMC和刺激内皮细胞释放NO来促进代谢性血管扩张(特别是在缺血期间)。这些研究将有助于全面了解局部对生理信号的反应是如何整合到血管壁中的，并将对理解运动的代谢反应这一广泛目标做出重大贡献。对运动潜在机制的充分理解与人类健康的许多领域相关。