Control of microvascular function by ion channels

离子通道控制微血管功能

• 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
• 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

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 对细胞外钙离子内流的影响。因此，神经元中撞击微血管的钙离子通透通道的调制 可以通过调节神经传递来改变微循环。一大批文献已经阐明了 血管平滑肌和内皮细胞钙信号在微血管功能调控中的作用。然而，在那里 在血管周围神经离子通道的功能和病理生理学方面仍存在显著的知识空白 微循环。目前的应用源于试点研究，该研究揭示了暂住者的新角色 受体潜能Melastatin 8(TRPM8)是感觉信号外的通道。我们提出一个耐人寻味的概念 部分外周交感神经(Sn)表达TRPM8通道。我们的数据表明，SNTRPM8 是氧化还原敏感的，并且由血管周围SNTRPM8通道介导的反应改变了血管阻力 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、药理学和高- 内容成像方法研究SnTRPM8激活增加血管的中心假说 通过钙依赖的儿茶酚胺神经传递而减少血管床的阻力和灌流 这一途径导致氧化应激诱导的血管功能障碍。为了解决这一假设，有三个 具体目标将被调查。目标1将验证血管周围SnTRPM8激活减少的假设 通过sn依赖的血管收缩的微循环。目标2将研究氧化还原诱发的SNTRPM8的假设 通道激活会增加血管阻力。目标3将探讨依赖于nTRPM8的概念 交感神经兴奋导致氧自由基引起的血管功能障碍和肾脏损伤。这个项目将 利用TRPM8通道的选择性药理调节剂和携带全局和sn特异性TRPM8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。