Hypertension and Prostanoid Signaling in the Subfornical Organ of the Brain

大脑穹窿下器官中的高血压和前列腺素信号传导

• 批准号: 7760718
• 负责人: Robin L Davisson
• 金额: $ 36.07万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-05 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760718
• 关键词: Angiotensin II; Attenuated; Automobile Driving; Baroreflex; Blood Pressure; Brain; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Coupled; Data; Dinoprostone; Dose; Electrophysiology (science); Essential Hypertension; Fluorescent Dyes; Functional disorder; Gene Transfer; Generations; Homeostasis; Hormonal; Hormones; Human; Hypertension; Image; In Vitro; Infusion procedures; Knock-in Mouse; Knock-out; Knockout Mice; Lead; Link; Maps; Measures; Mediating; Modeling; Molecular; Mus; NADPH Oxidase; Neural Pathways; Neurons; Output; Oxidants; Phase; Physiological; Plasma; Play; Predisposition; Production; Prosencephalon; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Reactive Oxygen Species; Receptor Gene; Receptor Inhibition; Relative (related person); Research; Role; Signal Pathway; Signal Transduction; Site; Source; Staging; Structure; Subfornical Organ; Testing; Urine; Vasopressins; Viral; Viral Genes; Work; base; blood pressure regulation; cerebrovascular; cyclooxygenase 1; drinking; immunocytochemistry; in vivo; inhibitor/antagonist; insight; interdisciplinary approach; neurophysiology; novel therapeutic intervention; oxidant stress; paraventricular nucleus; patch clamp; prevent; receptor; receptor expression; recombinase; reconstitution; response; spatiotemporal; voltage

PROJECT 1 (Davisson): Hypertension and prostanoid signaling in the subfornical organ of the brain There is compelling evidence that human hypertension is characterized by neurohumoral dysfunction, and inappropriate angiotensin II (Angll) signaling in the CNS is a primary culprit. The subfornical organ (SFO), a forebrain structure considered a key "gateway" to the CNS for circulating Angll, provides extensive inputs to the paraventricular nucleus (PVN) and its output neurons mediating sympathetic activation and release of hormones, e.g., vasopressin. Our work shows that excessive reactive oxygen species (ROS) signaling in SFO are critical in "slow-pressor" Angll hypertension, a subpressor Angll infusion model that recapitulates critical features of essential hypertension. However, the signaling mechanisms within the SFO by which Angll and oxidant products initiate the neurohumoral dysfunction leading to the blood pressure elevation are not clear. Cyclooxygenase (COX)-derived prostaglandins, such as prostaglandin E2 (PGE2), have long been implicated in the signaling pathways of Angll, but their role in critical mechanisms in the SFO underlying slow-pressor Angll hypertension has not been elucidated. Our preliminary data suggest a crucial role of COX-1-derived PGE2 acting on PGE2 EPi receptors (EPiR) in Angll slow pressor hypertension. Project 1 will test the central hvpothesis that PGE9 provides an essential link between Angll, ROS and the maladaptive changes that occur in the SFO-PVN axis which lead to neurohumoral dysfunction in the Ang-ll slow-pressor model. Aim 1 will test the hypothesis that AT, receptors, NADPH oxidase subunits and PGE2-related molecules are co-localized in PVN-projecting SFO neurons in a manner consistent with their functional interaction. Aim 2 will test the hypothesis that administration of slow pressor doses of Angll elicits C0X1- dependent PGE2 production in the SFO. This aim will also determine whether ROS production is upstream or downstream of PGE2. Aim 3 will use single-cell electrophysiology and ROS imaging to test the hypothesis that COX-1-derived PGE2 is required for the enhancement of Ca^* currents and ROS production induced by Angll in PVN-projecting SFO neurons. Aim 4 will test the hypothesis that EPiR in SFO are necessary and sufficient to confer susceptibility to slow-pressor Angll neurohumoral dysfunction and hypertension. We will use a newly developed conditional EPiR null mouse in which EPiR expression can be regionally reconstituted by local delivery of Cre recombinase.

项目 1（戴维森）：大脑穹窿下器官中的高血压和前列腺素信号传导 有令人信服的证据表明，人类高血压的特点是神经体液功能障碍，并且 中枢神经系统中不适当的血管紧张素 II (AngII) 信号传导是罪魁祸首。穹窿下器官 (SFO) 前脑结构被认为是中枢神经系统循环 Angll 的关键“门户”，为 室旁核（PVN）及其输出神经元介导交感神经的激活和释放 激素，例如加压素。我们的工作表明，过量的活性氧（ROS）信号传导 SFO 在“慢升压”Angll 高血压中至关重要，这是一种亚降压 Angll 输注模型，概括了 原发性高血压的关键特征。然而，SFO 内的信号机制 Angll和氧化剂产物引发神经体液功能障碍，导致血压升高 不清楚。环加氧酶 (COX) 衍生的前列腺素，如前列腺素 E2 (PGE2)，长期以来一直被认为是 与 Angll 的信号通路有关，但它们在 SFO 的关键机制中的作用 慢升压Angll高血压尚未阐明。我们的初步数据表明， COX-1 衍生的 PGE2 作用于 Angll 减缓升压性高血压中的 PGE2 EPi 受体 (EPiR)。项目1将 测试 PGE9 在 Angll、ROS 和适应不良之间提供重要联系的中心假设 SFO-PVN 轴发生的变化导致 Ang-II 慢升压神经元的神经体液功能障碍 模型。目标 1 将检验 AT、受体、NADPH 氧化酶亚基和 PGE2 相关的假设 分子以与其功能一致的方式共定位于 PVN 投射的 SFO 神经元中 相互作用。目标 2 将检验以下假设：施用缓慢升压剂量的 AngII 会引发 C0X1- SFO 中依赖的 PGE2 生产。这一目标还将决定 ROS 生产是上游还是 PGE2 的下游。目标 3 将使用单细胞电生理学和 ROS 成像来检验假设 COX-1 衍生的 PGE2 是增强 Ca^* 电流和 ROS 产生所必需的 PVN 投射 SFO 神经元中的 Angll。目标 4 将检验以下假设：SFO 中的 EPiR 是必要的并且 足以导致对慢升压Angll神经体液功能障碍和高血压的易感性。我们将 使用新开发的条件 EPiR 无效小鼠，其中 EPiR 表达可以区域性 通过局部递送 Cre 重组酶进行重组。