Mechanisms of Metabolic Vasodilation

横纹肌中血流和代谢率的调节密切相关，但具体使血管活性代谢物产生综合小动脉反应的途径仍然难以捉摸。 我们已经确定内皮细胞 (EC) 和 EC Ca 2 变化对于阻力小动脉中的代谢性血管舒张至关重要。 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条件下最为突出，即代谢性血管舒张的机制通过血流而改变。 这些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用于量化骨骼肌收缩期间 EC Ca 2 和小动脉直径的变化。 我们将根据我们的初步发现检验 3 个假设。 炒作。 I：在代谢性血管舒张中，EC Ca 2 变化的产生需要KATP 通道。 炒作。 II：EC Ca 2 变化对于所有血流条件下的代谢性血管舒张至关重要。 这些变化由两个部分组成——从细胞内储备动员的早期增加，以及依赖于细胞外钙源的振荡部分。 炒作。 IIl：（A部分）内皮来源的NO对缺血条件下发生的代谢性血管舒张有显着贡献，但在自由流动期间的反应中的重要性要小得多。 （B 部分）来自非内皮细胞的 nNOS 也通过直接影响 SMC 和刺激内皮细胞释放 NO 来促进代谢性血管舒张（特别是在缺血期间）。 这些研究将有助于普遍了解对生理信号的局部反应如何整合到血管壁中，并将为了解运动的代谢反应这一广泛目标做出重大贡献。 充分了解运动背后的机制与人类健康的许多领域相关。

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.