Control of microvascular function by ion channels

离子通道控制微血管功能

基本信息

批准号：
10201230
负责人：
Adebowale Adebiyi
金额：
$ 2.34万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-22 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10201230
关键词：
Ablation Acute Address Adrenergic Agents Anions Biological Markers Blood Pressure Blood Vessels Blood Volume Cardiovascular Diseases Catecholamines Cations Cells Chronic Cisplatin Data Disease Electrolytes Endothelial Cells Endothelium Exocytosis Experimental Models Functional disorder Generations Glomerular Filtration Rate Histology Hypertension Imaging Techniques Impairment In Vitro Injury to Kidney Ion Channel Kidney Kidney Diseases Kidney Failure Knowledge Lasers Life Literature Mediating Membrane Proteins Mesentery Microcirculation Microscopy Modeling Mus Myocardial Infarction Nerve Nerve Endings Neurons Neurotransmitter Receptor Norepinephrine Organ Oxidants Oxidation-Reduction Oxidative Stress PC12 Cells Pathway interactions Perfusion Peripheral Permeability Pharmacology Phenotype Physiological Physiology Pilot Projects Plasma Prevention Public Health Publishing Reactive Oxygen Species Regional Blood Flow Renal function Role Sensory Sensory Receptors Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Stress Stroke Sympathectomy System Techniques Telemetry Testing Time United States Vascular Diseases Vascular Smooth Muscle Vascular resistance Venous afferent nerve alpha-adrenergic receptor decubitus ulcer extracellular genetic approach hemodynamics hypoperfusion imaging approach in vivo insight kidney dysfunction mimetics multiphoton microscopy neurotransmission neurotransmitter release novel postsynaptic pressure presynaptic neurons receptor relating to nervous system renal damage response stem therapeutic target ultrasound microscopy vascular bed vascular injury vasoconstriction

项目摘要

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.

血管平滑肌细胞中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着改变，其机制可能会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细胞外 Ca2+ 内流。因此，调节影响微血管的神经元中的 Ca2+ 通透通道可以通过调节神经传递来改变微循环。大量文献阐明了其作用血管平滑肌和内皮细胞 Ca2+ 信号传导控制微血管功能。然而，有关于血管周围神经离子通道的功能和病理生理学仍然存在重大知识空白微循环。当前的应用源于试点研究，该研究揭示了瞬态的新作用感觉信号传导之外的受体电位 melastatin 8 (TRPM8) 通道。我们提出了一个有趣的概念外周交感神经 (sn) 的一个子集表达 TRPM8 通道。我们的数据表明 snTRPM8 对氧化还原敏感，血管周围 snTRPM8 通道介导的反应会改变血管阻力通过平滑肌细胞肾上腺素能系统。我们将使用一系列生理学知识；药理学；和高内容成像方法研究 snTRPM8 激活增加血管的中心假设阻力并通过 Ca2+ 依赖的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。为了解决这个假设，三个将调查具体目标。目标 1 将检验血管周围 snTRPM8 激活减少的假设通过 Sn 依赖性血管收缩来调节微循环。目标 2 将研究氧化还原诱发 snTRPM8 的假设通道激活增加血管阻力。目标 3 将探索 snTRPM8 依赖的概念交感神经兴奋会导致氧自由基引起的血管功能障碍和肾损伤。该项目将利用 TRPM8 通道的选择性药理调节剂和具有全局和 sn 特异性 TRPM8 的小鼠删除。研究微循环的技术包括时空超声、激光多普勒和多光子显微镜。