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：
10594479
负责人：
Adebowale Adebiyi
金额：
$ 24.44万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10594479
关键词：
Ablation Acute Address Anions Arterial Injury Biological Markers Blood Pressure Blood Vessels Blood Volume Cardiovascular Diseases Catecholamines Cations Cells Chemical Sympathectomy Chronic Cisplatin Data Diameter Disease Electrolytes Endothelial Cells Endothelium Exocytosis Experimental Models Functional disorder Generations Glomerular Filtration Rate Histology Hypertension Imaging Techniques Impairment Implant In Vitro Injury to Kidney Ion Channel Kidney Kidney Diseases Kidney Failure Knockout Mice Knowledge Lasers Life Literature Mediating Membrane Proteins Mesentery Microcirculation Modeling Mus Myocardial Infarction Myography Nerve Nerve Endings Neurons Neurosecretion Neurotransmitter Receptor Norepinephrine Norepinephrine Secretion Induction Organ Oxidants Oxidation-Reduction Oxidative Stress Induction PC12 Cells Pathway interactions Perfusion Peripheral Permeability 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 absorption afferent nerve alpha-adrenergic receptor cold stress decubitus ulcer extracellular genetic approach hemodynamics hypoperfusion in vivo insight kidney dysfunction mimetics mouse model multiphoton microscopy neural neurotransmission neurotransmitter release novel pharmacologic postsynaptic pressure presynaptic neurons receptor response stem therapeutic target ultrasound 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显着改变，其机制可能被放大或心血管和肾脏疾病减少。突触前神经末梢释放的神经递质是高度依赖细胞外 Ca2+ 内流。因此，调节神经元中的 Ca2+ 通透通道撞击微血管可以通过调节神经传递来改变微循环。大量文献已阐明了内皮和平滑肌 Ca2+ 通透性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学和病理生理学是不同的。不太了解。越来越多的证据表明，瞬时受体电位 melastatin 8 (TRPM8) 冷敏感神经元通道可能在其他细胞和组织（包括血管）中发挥多种功能。目前的应用源于初步研究，该研究揭示了 TRPM8 的新血管作用。我们的数据表明血管周围交感神经 (sn) 的一个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 snTRPM8 激活增加血管阻力的新中心假设并通过 Ca2+ 依赖性儿茶酚胺胞吐作用减少血管床灌注，并且该途径有助于脉管系统中活性氧的病理生理学。我们将调查是否：1) snTRPM8 通道激活通过改变微血管直径来损害血管床灌注，2) TRPM8- 依赖性交感神经兴奋有助于氧化应激引起的血管功能障碍和肾损伤。这该项目将利用 TRPM8 通道的选择性药理调节剂、化学交感神经切除术和条件性和全局 TRPM8 敲除小鼠模型。研究微血管功能的技术包括多光子显微镜、肌动描记术、时空超声和激光多普勒。