Pannexin 1 and sympathetic vasoconstriction

Pannexin 1 和交感血管收缩

• 批准号: 10407614
• 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/10407614
• 关键词: Adrenergic Receptor; Antihypertensive Agents; Arteries; Attenuated; Binding; Blood; Blood Pressure; Blood Vessels; Cells; Clinical; Communication; Data; Development; Electrophysiology (science); Epidemic; 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; 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; 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项目摘要 由于其与肥胖的密切相关，增长最快的高血压类型是对称驱动的 达到流行比例。在这种高血压的形式中，交感神经（SN）活性的影响 - 即 在SMC上释放去甲肾上腺素（NE）以在平滑肌细胞（SMC）上结合α-肾上腺素受体（α-AR） 增强了。 NE是一种潜在的血管收缩剂，可以大大增加血压。那，平滑肌 电阻动脉细胞是SN驱动高血压的主要部位。我们的PPG最近变得重要 理解α-AR介导的血管收缩途径的发现，这迫使我们重新思考 经典机制，交感神经会引起SMC收缩。在抵抗动脉中，我们发现 α-AR激活（而非其他血管收缩受体途径）诱导PANNEXIN 1（PANX1）通道 在SMC上打开以发布ATP。这项工作确定了PANX1衍生的ATP的关键功能作用，并提高了 关于交感神经与SMC之间相互作用的新问题。此外，我们的PPG最近 发现有效的抗高血压药物螺内酯直接在Panx1通道上起作用以降低血液 压力，独立于盐皮质激素受体。这项工作可能具有“揭露” panx1作为重要的 螺内酯的抗高血压作用的其他成分。一起，我们出版的和初步 数据提供了在此提案中检验的假设的前提：Pannexin 1链接同情 神经系统到动脉功能。我们提出了两个目的来检验这一假设。在特定目标1中，我们 假设Pannexin 1通道调节外周耐药性的交感神经控制 高血压。这个目标将与PANX1遗传敲除的同情高血压模型合并到 确定PANX1干预是否可以逆转高血压。其他PANX1过表达模型和 新的Panx1药物激活剂将有助于确定PANX1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与平滑肌之间的交流 细胞。我们将通过可视化ATP释放并刺激直接检查嘌呤能信号传导域 直接交感神经。翻译组成部分将我们的发现与没有和没有的人类 高血压。所有提议的淘汰小鼠都强调了实现这些目标的可行性 手头，为人类样品和强大的初步数据提供了IRB。项目2与 此P01上的其他项目为我们提供了探索新颖的药理学目标的机会 交感神经驱动的高血压无法单独实现。