Unit Control of Muscle Blood Flow

描述（由申请人提供）：我们的长期目标是为外周血管阻力调节的细胞信号通路提供新的见解。在运动过程中，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肌肉的血流量和动脉压力。阻力网络由嵌入肌肉中的小动脉及其位于组织外部的供给动脉（FA）组成。随着运动单位的招募和收缩活动的增加，血管舒张在小动脉上开始，并通过沿内皮细胞的细胞间信号传导（超极化）“上升”到FA，使周围的平滑肌细胞松弛。抵抗血管中分布着交感神经；因此，随着SNA的增加，小动脉和FA逐渐收缩。运动时，SNA会导致下游小动脉扩张，而上游FA收缩，从而限制肌肉血液流动。我们的工作假设是，上升（传导）血管舒张是由SNA调节的，以控制肌肉血流量，同时维持动脉压。我们的具体目标是：(1)确定启动血管升压的信号通路；(2)确定哪些离子通道是血管激活的起始和传导的基础；(3)确定SNA如何调节传导血管舒张。采用麻醉仓鼠牵开肌制备，刺激肌肉纤维收缩，用视频显微镜观察血管舒缩反应。将单个FA分离并加压，以记录血管舒张和SNA过程中的血管舒缩和电生理反应。潜在的信号通路研究使用特定的药物干预，细胞内记录和选择性破坏内皮或平滑肌功能。这些实验的发现将为身体表现的血管决定因素提供新的、机械的见解，并为理解因疾病、不活动和衰老而导致的身体工作能力下降奠定基础。这一见解将促进新策略的发展，以维持积极的生活方式，并从受损的身体工作能力中康复和恢复。

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.