Pannexin 1 and sympathetic vasoconstriction

Pannexin 1 和交感血管收缩

• 批准号: 10625327
• 负责人: Brant E Isakson
• 金额: $ 40.58万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625327
• 关键词: Adrenergic Receptor; Antihypertensive Agents; Arteries; Attenuated; Binding; Blood; Blood Pressure; Blood Vessels; Cannulations; Cells; Clinical; Communication; Data; Development; Electrophysiology (science); Epidemic; Evaluation; FDA approved; Genetic; Hand; Home; Human; Hypertension; In Situ; Inflammation; Institutional Review Boards; Intervention; Knock-out; Knockout Mice; Label; Link; Luciferases; Measurement; Measures; Mediating; Mesenteric Arteries; Messenger RNA; Mineralocorticoid Receptor; Modeling; Monitor; Mus; Nerve; Norepinephrine; Obese Mice; Obesity; Pathology; Pathway interactions; Peripheral Resistance; Pharmaceutical Preparations; Pharmacology; Physiology; Play; Positioning Attribute; Process; Proteins; Publishing; Purinoceptor; Receptor Activation; Reporter; Research; Resistance; Role; Sampling; Signal Transduction; Site; Smooth Muscle Myocytes; Spironolactone; Sympathetic Nervous System; Testing; Translating; Vasoconstrictor Agents; Visualization; Work; alpha-adrenergic receptor; arteriole; blood pressure elevation; blood pressure reduction; clinically significant; constriction; electric field; experimental study; hypertensive; indexing; inhibitor; insight; molecular targeted therapies; nerve supply; novel; overexpression; pharmacologic; preclinical study; pressure; receptor; response; synergism; vasoconstriction

PROJECT 2 PROJECT SUMMARY The fastest growing type of hypertension is sympathetically driven due to its close association with obesity, itself reaching epidemic proportions. In this form of hypertension, the effect of sympathetic nerve (SN) activity – i.e., release of norepinephrine (NE) to bind α-adrenergic receptors (α-AR) on smooth muscle cells (SMC) on SMC – is enhanced. NE is a potent vasoconstrictor and can strongly increase blood pressure. Thus, the smooth muscle cells of resistance arteries is a major site for SN-driven hypertension. Our PPG has recently made important discoveries in understanding the α−AR-mediated vasoconstriction pathway, which have forced us to re-think the classical mechanism whereby sympathetic nerve induces SMC constriction. In resistance arteries, we found that α-AR activation (and not other vasoconstriction receptor pathways) induced Pannexin 1 (Panx1) channel opening on SMC to release ATP. This work identifies a key functional role for Panx1-derived ATP, and raises new questions on the interaction between sympathetic nerve and SMCs. Furthermore, our PPG recently discovered that the potent anti-hypertensive drug spironolactone acts directly on Panx1 channels to lower blood pressure, independent of mineralocorticoid receptors. This work may have “unmasked” Panx1 as an important additional component to the anti-hypertensive effects of spironolactone. Together, our published and preliminary data provide the premise for the hypothesis tested in this proposal: Pannexin 1 links the sympathetic nervous system to arterial function. We propose two aims to test this hypothesis. In Specific Aim 1, we hypothesize that Pannexin 1 channels regulate sympathetic nerve control of peripheral resistance in hypertension. This aim will incorporate models of sympathetic hypertension with Panx1 genetic knockout to determine if Panx1 intervention can reverse high blood pressure. Additional Panx1 over-expression models and new Panx1 pharmacological activators will help determine whether Panx1 can modulate blood pressure. In Specific Aim 2, we ask further on the communication between sympathetic nerves and smooth muscle cells. We will examine the purinergic signaling domain directly, by visualizing ATP release and stimulating sympathetic nerves directly. A translational component will compare our findings to humans with and without hypertension. The feasibility of accomplishing these aims is underscored by all proposed knockout mice being in hand, an IRB in place for human samples, and the strong preliminary data. The integration of Project 2 with other Projects on this P01 provides us with an opportunity to explore a novel pharmacological target for sympathetic nerve-driven hypertension that could not have been achieved alone.

项目2项目概要 增长最快的高血压类型是交感神经驱动的，因为它与肥胖密切相关， 达到流行病的程度。在这种形式的高血压中，交感神经（SN）活动的影响--即， 释放去甲肾上腺素（NE）与平滑肌细胞（SMC）上的α-肾上腺素能受体（α-AR）结合， 增强了。NE是一种有效的血管收缩剂，可强烈升高血压。因此，平滑肌 阻力动脉细胞是SN驱动的高血压的主要部位。我们的PPG最近让 在了解α-AR介导的血管收缩通路方面的发现，迫使我们重新思考 交感神经诱导SMC收缩的经典机制。在阻力动脉中，我们发现， α-AR激活（而非其他血管收缩受体途径）诱导Pannexin 1（Panx 1）通道 打开SMC释放ATP。这项工作确定了Panx 1衍生ATP的关键功能作用，并提出了 交感神经与平滑肌细胞相互作用的新问题。此外，我们的PPG最近 发现强效抗高血压药物螺内酯直接作用于Panx 1通道， 压力，独立于盐皮质激素受体。这项工作可能“揭露”Panx 1作为一个重要的 安体舒通抗高血压作用的附加成分。我们已经公布的和初步的 数据提供了在该提议中测试的假设的前提：Pannexin 1连接交感神经系统。 神经系统到动脉功能。我们提出了两个目标来检验这一假设。在具体目标1中， 假设Pannexin 1通道调节交感神经对外周阻力控制， 高血压这一目标将结合Panx 1基因敲除的交感性高血压模型， 确定Panx 1干预是否可以逆转高血压。额外的Panx 1过表达模型和 新的Panx 1药理学激活剂将有助于确定Panx 1是否可以调节血压。在 具体目标2，我们进一步询问交感神经和平滑肌之间的通讯 细胞我们将通过观察ATP的释放和刺激， 交感神经直接。一个翻译组件将比较我们的发现与人类有和没有 高血压实现这些目标的可行性通过所有提出的基因敲除小鼠被证实是有效的来强调。 手，一个IRB在人体样本的地方，和强大的初步数据。项目2与 P01上的其他项目为我们提供了探索新的药理学靶点的机会， 交感神经驱动的高血压，这是无法单独实现的。