Control of microvascular function by ion channels

血管内皮细胞和平滑肌细胞连接后神经递质受体的激活调节 血管张力，并导致器官灌注量的显著变化，其机制可能被放大或 减少心血管和肾脏疾病。突触前神经末梢的神经递质释放 高度依赖细胞外钙离子内流。因此，神经元中钙离子通透通道的调制 冲击微血管可以通过调节神经传递来改变微循环。大量的文学作品都有 阐明内皮细胞和血管内皮细胞钙离子通透通道在微血管调控中的作用 功能。然而，微循环中血管周围神经离子通道的生理学和病理生理学 人们对此知之甚少。越来越多的证据表明，瞬时受体电位Melastatin 8(TRPM8)，a 冷敏感神经元通道可能在包括血管在内的其他细胞和组织中发挥多种功能。 目前的应用源于初步研究，发现了TRPM8的一个新的血管作用。我们的数据显示 部分血管周围交感神经(Sn)表达功能性和氧化还原敏感型TRPM8通道。 因此，我们建议研究新的中心假设，即激活SNTRPM8增加血管阻力 并通过钙依赖的儿茶酚胺胞吐减少血管床灌注量，这一途径 有助于血管系统中的活性氧物种的病理生理学。我们将调查是否：1) SnTRPM8通道激活通过改变微血管直径而损害血管床灌流，2)TRPM8- 依赖的交感神经兴奋导致氧化应激诱导的血管功能障碍和肾脏损伤。这 该项目将利用TRPM8通道的选择性药物调节剂，化学交感神经切除术，以及 有条件的和全局的TRPM8基因敲除小鼠模型。研究微血管功能的技术包括 多光子显微镜、肌肉造影术、渡越时间超声和激光多普勒。

Activation of post-junctional neurotransmitter receptors in vascular endothelial and smooth muscle cells modulates vascular tone and causes significant alterations in organ perfusion, mechanisms of which may be amplified or diminished in cardiovascular and kidney disease. Neurotransmitter release from presynaptic nerve terminals is highly dependent on extracellular Ca2+ influx. Thus, modulation of Ca2+-permeable channels in neurons that impinge on microvessels can alter microcirculation by regulating neurotransmission. A large body of literature has elucidated the role of endothelial and smooth muscle Ca2+-permeable channels in the control of microvascular function. However, the physiology and pathophysiology of perivascular nerve ion channels in microcirculation are poorly understood. Accumulating evidence suggests that the transient receptor potential melastatin 8 (TRPM8), a cold-sensitive neuronal channel may exert multiple functions in other cells and tissues, including blood vessels. The current application stems from pilot studies that uncovered a new vascular role for TRPM8. Our data suggest that a subset of perivascular sympathetic nerves (sn) expresses functional and redox-sensitive TRPM8 channels. Hence, we propose to study the novel central hypothesis that snTRPM8 activation increases vascular resistance and reduces vascular bed perfusion via Ca2+-dependent catecholamine exocytosis and that this pathway contributes to the pathophysiology of reactive oxygen species in the vasculature. We will investigate whether: 1) snTRPM8 channel activation impairs vascular bed perfusion by altering microvascular diameter and 2) TRPM8- dependent sympathoexcitation contributes to oxidative stress-induced vascular dysfunction and kidney injury. This project will utilize selective pharmacological modulators of TRPM8 channels, chemical sympathectomy, and conditional and global TRPM8 knockout mouse models. Techniques to investigate microvascular function include multiphoton microscopy, myography, transit-time ultrasound, and laser-Doppler.