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: 10116452
• 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/10116452
• 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.

精确控制整个身体的动脉直径对于维持灌注压和 血液流向重要器官，如大脑。L型电压依赖性钙通道的钙内流 血管平滑肌细胞（VDCCs）传统上被认为是动脉平滑肌（ASM）中主要的Ca 2+进入途径， 控制收缩和动脉直径的调节。在这里，我们提供了直接的证据， 在某些类型的ASM中主要的Ca 2+内流途径-瞬时受体电位香草酸1（TRPV 1）通道， 一种“非选择性”的Ca 2+渗透性离子通道，通常参与感觉神经中的伤害感受。使用 “光学膜片钳”技术，我们提供了第一个测量的钙离子流入通过单一的TRPV 1 通道（“sparklets”）。重要的是，我们的初步数据还表明，ASM TRPV 1 通道通过激活β 1-肾上腺素能受体（β 1-AR）-主要的血管收缩途径， 交感神经系统（SNS）。SNS在维持脑血流量（CBF）中的作用特别重要。 在急性低血压发作期间是重要的（例如，出血性休克），并部分通过E1- 外周组织中AR介导的血管收缩。我们的总体假设是，在应对急性 血压降低，具有ASM TRPV 1通道的非脑动脉收缩调节血管 我们发现缺乏TRPV 1通道的脑动脉对血液重新分配的阻力。 在目标1中，我们探索了TRPV 1被ARs激活的基础。这一目标的目标是解开 ASM 1-ARs、ASM TRPV 1通道、Ca 2+信号传导和动脉直径之间的联系。我们相信 TRPV 1的差异表达和TRPV 1-AR配体对该通道的激活在细胞凋亡中起重要作用。 SNS调节动脉平滑肌Ca ~（2+）和动脉直径。具体来说，我们测试的假设， TRPV 1通道激活通过多种途径促进细胞内Ca 2+增加和血管收缩 包括：1）通过TRPV 1通道直接Ca 2+进入，2）TRPV 1介导的阳离子内流，膜 潜在的（VM）去极化和增强的VDCC活性。在目标2中，我们将联合收割机体内测量 动脉直径，ASM Ca 2+和CBF，以阐明TRPV 1通道在促进维持 血压急性下降时的CBF，类似失血性休克。 总之，本提案旨在提供前所未有的TRPV 1通道影响解决方案 动脉直径和脑血流量确定ASM TRPV 1在急性降低期间促进CBF的关键作用 在血压有可能提供丰富的新信息的巨大利益的个人休克 患者和整个社会。