TRPV1 channels in arterial smooth muscle: a novel vasoconstrictor mechanism to promote maintained cerebral blood flow during acute decreases in blood pressure

动脉平滑肌中的 TRPV1 通道：一种新型血管收缩机制，可在血压急性下降期间促进维持脑血流

• 批准号: 9903431
• 负责人: GEORGE C WELLMAN
• 金额: $ 50.71万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903431
• 关键词: 6 year old; Acute; Adrenergic Receptor; Afferent Neurons; American; Arteries; Blood; Blood Pressure; Blood Vessels; Blood flow; Brain; Calcium; Caliber; Cations; Cause of Death; Cerebrovascular Circulation; Cerebrovascular system; Data; Drops; Goals; Head; Hemorrhage; Hemorrhagic Shock; Hypotension; Individual; Injury; Ion Channel; Ligands; Maintenance; Measurement; Measures; Mediating; Membrane Potentials; Metabolic; Muscle Cells; Nociception; Norepinephrine; Nutrient; Optics; Organ; Oxygen; Pain Research; Patch-Clamp Techniques; Pathologic; Pathway interactions; Patients; Perfusion; Peripheral; Permeability; Physiological; Play; Preparation; Regulation; Reporter; Resolution; Role; Shock; Shunt Device; Signal Transduction; Smooth Muscle; Societies; Stimulus; Sympathetic Nervous System; Systemic blood pressure; Testing; Tissues; Translating; Trauma; Vanilloid; Vascular resistance; Vasoconstrictor Agents; afferent nerve; blood pressure reduction; cell type; cerebral artery; constriction; design; differential expression; improved outcome; in vivo; innovation; lens; mouse model; neurotransmission; novel; pressure; protective effect; receptor; response; vascular bed; vasoconstriction; voltage

Precise control of arterial diameter throughout the body is essential to maintain perfusion pressure and blood flow to vital organs, such as the brain. Ca2+ influx through L-type voltage-dependent Ca2+ channels (VDCCs) has traditionally been viewed as the major Ca2+ entry pathway in arterial smooth muscle (ASM) that controls contraction and the regulation of arterial diameter. Here, we provide direct evidence for a second major Ca2+ entry pathway in some types of ASM—the transient receptor potential vanilloid 1 (TRPV1) channel, a “non-selective” Ca2+-permeable ion channel typically involved in nociception in sensory nerves. Using “optical patch-clamping” techniques, we provide the first measurements of Ca2+ influx through single TRPV1 channels (“sparklets”). Importantly, our preliminary data also demonstrate engagement of ASM TRPV1 channels by activation of 1-adrenergic receptors (1-ARs)—the major vasoconstrictor pathway of the sympathetic nervous system (SNS). The role of the SNS in maintaining cerebral blood flow (CBF) is particularly important during episodes of acute hypotension (e.g., hemorrhagic shock) and is achieved in part through 1- AR–mediated vasoconstriction in peripheral tissue. Our overarching hypothesis is that, in response to acute decreases in blood pressure, constriction of non-brain arteries possessing ASM TRPV1 channels tunes vascular resistance to redistribute blood to cerebral arteries, which we have found to lack TRPV1 channels. Within Aim 1, we explore the basis of TRPV1 activation by -ARs. The goal of this aim is to unravel the linkages between 1-ARs, ASM TRPV1 channels, Ca2+ signaling and arterial diameter. We believe the differential expression of TRPV1 and the activation of this channel by 1-AR ligands play important roles in the regulation ASM Ca2+ and arterial diameter by the SNS. Specifically, we test the hypothesis that SNS-evoked TRPV1 channel activation promotes increased global cytosolic Ca2+ and vasoconstriction via multiple pathways including: 1) direct Ca2+ entry through TRPV1 channels and, 2) TRPV1-mediated cation influx, membrane potential (VM) depolarization and enhanced VDCC activity. In Aim 2, we combine in vivo measurements of arterial diameter, ASM Ca2+ and CBF to elucidate the role of TRPV1 channels in promoting the maintenance of CBF during acute decreases in blood pressure that mimic hemorrhagic shock. In summary, this proposal is designed to provide unprecedented resolution of TRPV1 channel impact on arterial diameter and CBF. Identifying a key role for ASM TRPV1 in promoting CBF during acute decreases in blood pressure has the potential to provide a wealth of new information of great benefit to individual shock patients and our society at large.

精确控制全身动脉直径对于维持灌注压和 血液流向重要器官，例如大脑。 Ca2+ 通过 L 型电压依赖性 Ca2+ 通道流入 (VDCC) 传统上被视为动脉平滑肌 (ASM) 中主要的 Ca2+ 进入途径， 控制收缩和动脉直径的调节。在这里，我们提供第二个直接证据 某些类型的 ASM 中主要的 Ca2+ 进入途径——瞬时受体电位香草酸 1 (TRPV1) 通道， 一种“非选择性”Ca2+ 渗透性离子通道，通常参与感觉神经的伤害感受。使用 “光学膜片钳”技术，我们通过单个 TRPV1 首次测量 Ca2+ 流入 频道（“小火花”）。重要的是，我们的初步数据还表明 ASM TRPV1 的参与 通过激活α1-肾上腺素能受体（α1-AR）来激活通道——α1-肾上腺素能受体的主要血管收缩途径 交感神经系统（SNS）。 SNS 在维持脑血流 (CBF) 方面的作用尤其重要 在急性低血压（例如失血性休克）发作期间很重要，部分是通过 1- 实现的 AR 介导的外周组织血管收缩。我们的总体假设是，为了应对急性 血压降低，具有 ASM TRPV1 通道的非脑动脉收缩，调节血管 血液重新分配到脑动脉的阻力，我们发现脑动脉缺乏 TRPV1 通道。 在目标 1 中，我们探索了 α-AR 激活 TRPV1 的基础。这一目标的目标是解开 α1-AR、ASM TRPV1 通道、Ca2+ 信号传导和动脉直径之间的联系。我们相信 TRPV1 的差异表达和 α1-AR 配体对该通道的激活在 通过 SNS 调节 ASM Ca2+ 和动脉直径。具体来说，我们测试了 SNS 诱发的假设 TRPV1 通道激活通过多种途径促进整体胞质 Ca2+ 增加和血管收缩 包括：1) 通过 TRPV1 通道直接 Ca2+ 进入，2) TRPV1 介导的阳离子流入、膜 潜在（VM）去极化和增强的 VDCC 活性。在目标 2 中，我们结合了体内测量 动脉直径、ASM Ca2+ 和 CBF，以阐明 TRPV1 通道在促进维持 CBF 期间血压急剧下降，类似于失血性休克。 总之，该提案旨在提供前所未有的 TRPV1 通道影响解决方案 与动脉直径和CBF有关。确定 ASM TRPV1 在急性下降期间促进 CBF 的关键作用 血压有可能提供大量新信息，对个体休克大有裨益 患者和整个社会。