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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：
10591881
负责人：
Adebowale Adebiyi
金额：
$ 5.81万
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：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10591881
关键词：
Ablation Acute Address Anions Biological Markers Blood Pressure Blood Vessels Blood Volume Caliber Cardiovascular Diseases Catecholamines Cations Cells Chemical Sympathectomy 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 Knockout Mice Knowledge Lasers Life Literature Mediating Membrane Proteins Mesentery Microcirculation Microscopy Modeling Mus Myocardial Infarction Myography 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 Receptors Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Stroke Sympathectomy System Techniques Telemetry Testing Time Tissues United States Vascular Diseases Vascular Endothelium Vascular Smooth Muscle Vascular resistance Venous afferent nerve alpha-adrenergic receptor cold stress decubitus ulcer extracellular genetic approach hemodynamics hypoperfusion in vivo insight kidney dysfunction mimetics mouse model multiphoton microscopy neurotransmission neurotransmitter release novel postsynaptic pressure presynaptic neurons receptor relating to nervous system response stem therapeutic target ultrasound ultrasound microscopy vascular bed vascular injury vasoconstriction

项目摘要

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.

血管内皮细胞和平滑肌细胞中连接后神经递质受体的激活调节血管张力，并导致器官灌注的显著改变，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于细胞外Ca 2+内流。因此，调节神经元中的Ca 2+渗透通道，撞击微血管可通过调节神经传递改变微循环。大量的文学作品阐明了内皮和平滑肌Ca 2+渗透通道在微血管控制中的作用，功能然而，微循环中血管周围神经离子通道的生理和病理生理学是微循环的重要组成部分。不太了解。越来越多的证据表明，瞬时受体电位melastatin 8（TRPM 8），冷敏感神经元通道可以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TRPM 8的新血管作用。我们的数据表明血管周围交感神经（sn）的子集表达功能性和氧化还原敏感性TRPM 8通道。因此，我们建议研究snTRPM 8激活增加血管阻力的新中心假设并通过Ca 2+依赖的儿茶酚胺胞吐作用减少血管床灌注，有助于脉管系统中活性氧的病理生理学。我们将调查是否：1） snTRPM 8通道激活通过改变微血管直径损害血管床灌注，以及2）TRPM 8- 依赖性交感神经兴奋导致氧化应激诱导的血管功能障碍和肾损伤。这该项目将利用TRPM 8通道的选择性药理学调节剂，化学交感神经切除术，条件和整体TRPM 8敲除小鼠模型。研究微血管功能的技术包括多光子显微镜检查、肌造影术、渡越时间超声和激光多普勒。