Cav-1.TRPV4 regulation of endothelial function in small pulmonary arteries

Cav-1.TRPV4对小肺动脉内皮功能的调节

• 批准号: 10394403
• 负责人: Swapnil K. Sonkusare
• 金额: $ 49.75万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394403
• 关键词: Adenosine Triphosphate; Agonist; Binding; Caveolae; Chronic; Complex; Data; Development; Diagnosis; Disease; Endothelial Cells; Endothelium; Event; Exposure to; Foundations; Functional disorder; Human; Hypoxia; Impairment; Individual; Intervention Studies; Knock-out; Knockout Mice; Lung; Mediating; Mus; Myelin P2 Protein; NOS3 gene; Nitric Oxide; Pathologic; Patients; Peroxonitrite; Progressive Disease; Protein Kinase C; Pulmonary Circulation; Pulmonary Hypertension; Pulmonary artery structure; Purinergic P2 Receptors; Purinoceptor; Reactive Nitrogen Species; Receptor Activation; Regulation; Reporting; Rest; Scaffolding Protein; Signal Pathway; Signal Transduction; Signaling Molecule; Superoxides; Systolic Pressure; Testing; Therapeutic; Therapeutic Intervention; Vanilloid; Vasodilation; Vasodilator Agents; Ventricular; base; caveolin 1; design; disease prognosis; endothelial dysfunction; human subject; improved; insight; member; mortality; mouse model; new therapeutic target; novel; novel therapeutic intervention; pulmonary arterial hypertension; pulmonary arterial pressure; receptor; shear stress; vasoconstriction

Abstract Pulmonary arterial hypertension (PAH) is a disease of pulmonary vasculature with a high mortality rate of up to 45% three years after diagnosis. PAH is often associated with the loss of endothelium-dependent vasodilation, which has long been thought to be a major contributor to development of PAH. However, the underlying mechanisms for the loss of endothelium-dependent vasodilation in PAH remain unclear, particularly in the native endothelium from small pulmonary arteries (PAs) that control pulmonary arterial pressure. We recently showed that endothelial TRPV4 (transient receptor potential vanilloid 4) channels are key regulators of endothelium- dependent vasodilation in PAs. In this application, we provide novel preliminary data that endothelial TRPV4 channels regulate resting pulmonary arterial pressure (PAP), and are impaired in PAH. Moreover, we show that scaffolding protein caveolin-1 provides a signaling platform for protein kinase C (PKC)-dependent regulation of TRPV4 channels, a mechanism that is defective in PAH. Interestingly, two different peroxynitrite scavengers restored endothelial TRPV4 channel activity in PAH, suggesting that peroxynitrite may be a key contributor to dysfunction of TRPV4 channel function. Additionally, exogenous peroxynitrite also impaired caveolin-1·PKC regulation of endothelial TRPV4 channel function. We, therefore, hypothesize that peroxynitrite-induced impairment in caveolin-1·PKC regulation of TRPV4 channel function contributes to the loss of endothelium- dependent vasodilation in PAH. In Specific Aim 1, we will use PAs from endothelium-specific TRPV4 and caveolin-1 knockout mice and human lungs to define a novel caveolin-1·PKC·TRPV4 vasodilator signaling complex that controls endothelial regulation of PAP. In Specific Aim 2, we will test the hypothesis that elevated peroxynitrite levels disrupt caveolin-1·PKC·TRPV4 vasodilator signaling complex in PAH. We will also determine whether lowering peroxynitrite levels in PAH reduces PAP in a TRPV4-dependent manner. These studies will establish that abnormalities in endothelial TRPV4 channels in small PAs contribute to PAH, and lay the foundation for novel therapeutic strategies to rescue endothelial TRPV4 channel function.

抽象的 肺动脉高压（PAH）是一种肺血管疾病，死亡率高至 诊断三年后45％。 PAH通常与内皮依赖性血管舒张的丧失有关， 长期以来，人们一直认为这是PAH发展的主要贡献者。但是，基础 PAH中依赖内皮依赖性血管舒张的机制尚不清楚，尤其是在天然中 来自控制肺动脉压力的小肺动脉（PA）的内皮。我们最近显示 该内皮TRPV4（瞬态接收器电势4）通道是内皮的关键调节剂 pA中的依赖性血管舒张。在此应用程序中，我们提供了内皮TRPV4的新型初步数据 通道调节静静脉动脉压（PAP），并在PAH中受损。而且，我们表明 脚手架蛋白小窝蛋白1为蛋白激酶C（PKC）依赖性调节提供了信号平台 TRPV4通道，一种在PAH中有缺陷的机制。有趣的是，两个不同的过氧氮气清除剂 PAH中恢复的内皮TRPV4通道活性 TRPV4通道功能的功能障碍。此外，外源过氧氮硝酸盐也损害了小窝蛋白-1·PKC 内皮TRPV4通道函数的调节。因此，我们假设过氧亚硝酸盐诱导 Caveolin-1·PKC调节TRPV4通道功能的损伤有助于山上的丧失 PAH中的依赖性血管舒张。在特定目标1中，我们将使用内皮特异性TRPV4和 可爱素-1敲除小鼠和人肺，以定义一种新型的小窝蛋白-1·PKC·Trpv4血管扩张剂信号传导 控制PAP的内皮调节的复合物。在特定的目标2中，我们将测试升高的假设 过氧亚硝酸盐水平破坏小窝蛋白-1·PKC·TRPV4血管扩张剂信号传导复合物中的PAH。我们还将确定 PAH中降低过氧亚硝酸盐水平是否以TRPV4依赖性方式降低PAP。这些研究会 确定小PA的内皮TRPV4通道异常有助于PAH，并放置 挽救内皮TRPV4通道功能的新型治疗策略基金会。