Control of microvascular function by ion channels

血管平滑肌细胞连接后神经递质受体的激活调节血管张力 并引起器官灌注的显著改变，其机制可能在 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于 对细胞外Ca 2+内流的影响。因此，在神经元中影响微血管的Ca 2+渗透通道的调节 通过调节神经传递改变微循环。大量的文献已经阐明了 血管平滑肌和内皮细胞Ca 2+信号在微血管功能控制中的作用。但 在血管周围神经离子通道的功能和病理生理学方面， 微循环目前的应用源于试点研究，这些研究揭示了瞬变的新作用 受体电位melastatin 8（TRPM 8）通道外的感觉信号。我们提出了一个有趣的概念 外周交感神经（sn）的子集表达TRPM 8通道。我们的数据表明，snTRPM 8 是氧化还原敏感的，并且由血管周围snTRPM 8通道介导的反应改变血管阻力 通过平滑肌细胞肾上腺素能系统。我们将使用生理学、药理学和高- 内容成像方法来研究snTRPM 8激活增加血管生成的中心假设 阻力，并通过Ca 2+依赖性儿茶酚胺神经传递减少血管床灌注， 该途径有助于氧化应激诱导的血管功能障碍。为了解决这个问题，三 将研究具体目标。目的1将检验血管周围snTRPM 8活化降低血管内皮细胞增殖的假设。 通过Sn依赖性血管收缩的微循环。目的2将研究氧化还原诱导的snTRPM 8 通道激活增加血管阻力。目的3将探讨snTRPM 8依赖性的概念， 交感神经兴奋导致氧自由基诱导的血管功能障碍和肾损伤。该项目将 利用TRPM 8通道的选择性药理学调节剂和具有全局和sn特异性TRPM 8的小鼠 删除。研究微循环的技术包括渡越时间超声、激光多普勒和多光子 显微镜

Activation of post-junctional neurotransmitter receptors in vascular smooth muscle cells modulates vascular tone and causes significant alterations in organ perfusion, mechanisms of which may be amplified or reduced in cardiovascular and renal 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 vascular smooth muscle and endothelial cell Ca2+ signaling in the control of microvascular function. However, there remains a significant knowledge gap on the function and pathophysiology of perivascular nerve ion channels in microcirculation. The current application stems from pilot studies that uncovered a new role for the transient receptor potential melastatin 8 (TRPM8) channels outside of sensory signaling. We propose an intriguing concept that a subset of peripheral sympathetic nerves (sn) expresses TRPM8 channels. Our data suggest that snTRPM8 is redox-sensitive and that the responses mediated by perivascular snTRPM8 channels alter vascular resistance via smooth muscle cell adrenergic system. We will use a repertoire of physiological; pharmacological; and high- content imaging approaches to study the central hypothesis that snTRPM8 activation increases vascular resistance and reduces vascular bed perfusion via Ca2+-dependent catecholamine neurotransmission and that this pathway contributes to oxidative stress-induced vascular dysfunction. To address this hypothesis, three specific aims will be investigated. Aim 1 will test the hypothesis that perivascular snTRPM8 activation reduces microcirculation via sn-dependent vasoconstriction. Aim 2 will study the hypothesis that redox-evoked snTRPM8 channel activation increases vascular resistance. Aim 3 will explore the concept that snTRPM8-dependent sympathoexcitation contributes to oxyradical-induced vascular dysfunction and renal damage. This project will utilize selective pharmacological modulators of TRPM8 channels and mice with global and sn-specific TRPM8 deletion. Techniques to investigate microcirculation include transit-time ultrasound, laser-Doppler, and multiphoton microscopy.