Unit Control of Muscle Blood Flow

描述（由申请人提供）：我们的长期目标是对外周血管阻力调节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控制阻力血管的直径来决定运动期间的肌肉血流量和动脉压。 阻力网络由嵌入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，血管舒张在小动脉上启动，并通过信号的细胞间传导（超极化）沿内皮沿着“上升”到FA，从而松弛周围的平滑肌细胞。 阻力血管布满交感神经;因此，随着SNA的增加，小动脉和FA逐渐收缩。 在运动期间，SNA在下游小动脉中占主导地位，而在上游FA中占主导地位，从而限制了肌肉血流。 我们的工作假设是，上行性（传导性）血管舒张是由SNA调节的，以在维持动脉压的同时调节肌肉血流量。 我们的具体目标是：（1）确定启动上行性血管调节的信号通路;（2）确定哪些离子通道是血管调节启动和传导的基础;（3）确定SNA如何调节传导性血管舒张。 在麻醉仓鼠中使用牵开肌制备物，刺激肌纤维收缩，并使用视频显微镜观察血管扩张反应。 隔离单个FA并加压，以记录进行血管舒张和SNA期间的血管扩张和电生理反应。 使用特定的药理学干预、细胞内记录和选择性破坏内皮或平滑肌功能来研究潜在的信号传导途径。 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制性见解，并加强理解疾病，不活动和衰老引起的身体工作能力下降的基础。 这一见解将促进发展新的战略，以保持积极的生活方式，以及康复和恢复受损的体力劳动能力。

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.