Unit Control of Muscle Blood Flow

描述(由申请人提供)：我们的长期目标是为调节外周血管阻力的细胞信号通路提供新的见解。骨骼肌收缩和交感神经活动(SNA)之间的相互作用通过调节阻力血管的直径来决定运动过程中的肌肉血流量和动脉压。阻力网络由嵌在肌肉内的小动脉及其位于组织外部的供血动脉(FA)组成。随着运动单位募集和收缩活动的增加，小动脉上的血管扩张被启动，并通过沿着内皮细胞对细胞的信号传导(超极化)“上升”到FA，该信号松弛周围的平滑肌细胞。阻力血管被交感神经包裹，因此，随着SNA的增加，小动脉和FA逐渐收缩。在运动中使用SNA时，下游小动脉的扩张占优势，而上游FA的收缩占优势，从而限制肌肉血流。我们的工作假设是，在维持动脉压的同时，上行(传导的)血管扩张是由SNA调节的，以控制肌肉血流。我们的具体目标是：(1)确定启动(S)上行血管舒缩的信号通路(S)；(2)确定启动和传导血管舒缩的离子通道；以及(3)确定SNA如何调节血管扩张。使用麻醉仓鼠的牵引肌制剂，刺激肌肉纤维收缩，并用视频显微镜观察血管舒缩反应。分离和加压单个FA，以记录在传导血管扩张和SNA过程中的血管运动和电生理反应。使用特定的药物干预、细胞内记录和选择性地破坏内皮或平滑肌功能来研究潜在的信号通路。这些实验的发现将为身体表现的血管决定因素提供新的、机械性的见解，并为理解疾病、不活动和衰老导致的体力工作能力下降奠定基础。这一见解将促进制定新的战略，以维持积极的生活方式，并从受损的体力工作能力中恢复和康复。

DESCRIPTION (provided by applicant): Our long term objectives are to provide new insight into the cellular signaling pathways that underlie the regulation of peripheral vascular resistance. The interaction between skeletal muscle contractions and sympathetic nerve activity (SNA) determines muscle blood flow and arterial pressure during exercise through governing the diameter of resistance vessels. The resistance network is comprised of arterioles embedded within the muscle and their feed arteries (FA) located extemal to the tissue. As motor unit recruitment and contractile activity increase, vasodilation is initiated on arterioles and "ascends" into FA via cell-to-cell conduction of a signal (hyperpolarization) along the endothelium that relaxes surrounding smooth muscle cells. Resistance vessels are invested with sympathetic nerves; thus, arterioles and FA constrict progressively as SNA increases. With SNA during exercise, dilation prevails in downstream arterioles while constriction prevails in upstream FA, which thereby restricts muscle blood flow. Our working hypothesis is that ascending (conducted) vasodilation is modulated by SNA to govem muscle blood flow while maintaining arterial pressure. Our Specific Aims are to: (1) Determine the signaling pathway(s) that initiate(s) ascending vasodUation; (2) Determine which ion channels underlie the initiation and the conduction of vasodUation; and (3) Determine how SNA modulates conducted vasodilation. Using the retractor muscle preparation in anesthetized hamsters, muscle fibers are stimulated to contract and vasomotor responses are observed using video microscopy. Individual FA are isolated and pressurized to record vasomotor and electrophysiological responses during conducted vasodilation and SNA. Underlying signaling pathways are investigated using specific pharmacological interventions, intracellular recording, and selective disruption of endothelium or smooth muscle function. Findings from these experiments will provide new, mechanistic insight into vascular determinants of physical performance and strengthen the foundation for understanding decrements in physical work capacity that occur with disease, inactivity, and aging. This insight will promote the development of novel strategies for the maintenance of an active lifestyle as well as rehabilitation and recovery from impaired physical work capacity.