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的结节后神经递质受体的激活调节血管张力并引起器官灌注的重大改变，其机制可能会被放大或心血管和肾脏疾病减少。神经递质从突触前神经终端释放高度取决于细胞外Ca2+流入。因此，在神经元中Ca2+可渗透通道的调节微血管会通过调节神经传递来改变微循环。大量文学有阐明了内皮和平滑肌Ca2+可渗透通道在微血管控制中的作用功能。然而，微循环中血管周神经通道的生理和病理生理学是理解不佳。积累的证据表明，瞬时受体电势曲霉蛋白8（TRPM8），A 冷敏感性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。当前的应用源于试验研究，该研究发现了TRPM8的新血管作用。我们的数据暗示血管周围交感神经（SN）的子集表达功能性和氧化还原敏感的TRPM8通道。因此，我们建议研究新的中心假设，即SNTRPM8激活增加了血管抗性并通过Ca2+依赖性儿茶酚胺胞吐作用来减少血管床灌注，并且该途径有助于脉管系统中活性氧的病理生理。我们将调查是否：1） SNTRPM8通道激活通过改变微血管直径和2）TRPM8-损害血管床灌注依赖性交感神经促进氧化应激引起的血管功能障碍和肾脏损伤。这项目将利用TRPM8通道，化学交感神经切除术和条件和全局TRPM8敲除鼠标模型。研究微血管功能的技术包括多光子显微镜，肌电图，运输时间超声和激光多普勒。