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: 10621152
• 负责人: Swapnil K. Sonkusare
• 金额: $ 48.75万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621152
• 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; NOS3 gene; Nitric Oxide; Pathogenesis; Pathologic; Patients; Peroxonitrite; Progressive Disease; Protein Kinase C; Pulmonary Circulation; Pulmonary Hypertension; Pulmonary artery structure; Purinergic P2 Receptors; Purinoceptor; Reaction; Reactive Nitrogen Species; Receptor Activation; Regulation; Reporting; Rest; Scaffolding Protein; Signal Pathway; Signal Transduction; Signaling Molecule; Superoxides; Systolic Pressure; TRPV channel; Testing; Therapeutic; Therapeutic Intervention; Vanilloid; Vasodilation; Vasodilator Agents; Ventricular; 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，死亡率高达 诊断三年后为 45%。 PAH 通常与内皮依赖性血管舒张功能的丧失有关， 长期以来，它一直被认为是 PAH 发展的主要贡献者。然而，底层 PAH 中内皮依赖性血管舒张功能丧失的机制仍不清楚，特别是在天然药物中 来自控制肺动脉压的小肺动脉（PA）的内皮细胞。我们最近展示了 内皮 TRPV4（瞬时受体电位香草酸 4）通道是内皮细胞的关键调节因子 PA 中的依赖性血管舒张。在此应用中，我们提供了新的初步数据，即内皮 TRPV4 通道调节静息肺动脉压 (PAP)，在 PAH 中受损。此外，我们表明 支架蛋白 Caveolin-1 为蛋白激酶 C (PKC) 依赖性调节提供信号平台 TRPV4 通道，PAH 中存在缺陷的一种机制。有趣的是，两种不同的过氧亚硝酸盐清除剂 恢复 PAH 中的内皮 TRPV4 通道活性，表明过氧亚硝酸盐可能是 PAH 的关键贡献者 TRPV4通道功能障碍。此外，外源性过氧亚硝酸盐也会损害caveolin-1·PKC 内皮 TRPV4 通道功能的调节。因此，我们假设过氧亚硝酸盐诱导 Caveolin-1·PKC 对 TRPV4 通道功能的调节受损导致内皮细胞损失 PAH 中的依赖性血管舒张。在具体目标 1 中，我们将使用来自内皮特异性 TRPV4 的 PA 和 Caveolin-1 敲除小鼠和人肺定义了一种新型的 Caveolin-1·PKC·TRPV4 血管舒张信号传导 控制 PAP 内皮调节的复合物。在具体目标 2 中，我们将检验以下假设： 过氧亚硝酸盐水平会破坏 PAH 中的 Caveolin-1·PKC·TRPV4 血管舒张信号复合物。我们还将确定 降低 PAH 中的过氧亚硝酸盐水平是否会以 TRPV4 依赖性方式降低 PAP。这些研究将 确定小 PA 中内皮 TRPV4 通道的异常导致 PAH，并奠定了 为挽救内皮TRPV4通道功能的新治疗策略奠定了基础。