Angiotensin-II, Hypothalamic Inflammation and Neurogenic Hypertension

描述（由申请人提供）：高血压是一种流行性健康问题，也是心血管疾病的主要风险因素，心血管疾病是美国的主要死亡原因。许多形式的高血压都是神经源性的;然而，神经源性高血压发生和进展的神经机制尚未完全了解。血管紧张素II（Ang-II）是肾素-血管紧张素系统的效应肽，是一种强有力的介导因子 在大脑中具有多效性的心血管功能。已知Ang-II可诱导 通过激活许多外周组织和大脑中的血管紧张素1a型受体（AT 1a）来引起炎症，这被认为有助于其高血压作用。与此一致，高血压除了伴随增强的肾素-血管紧张素系统活性外，还与轻度炎症状态相关。一个关键部位 Ang-II在脑内的作用是下丘脑的室旁核（PVN），其密集地表达AT 1a并整合进出对心血管功能和交感神经活动的调节至关重要的脑区域的信号。本研究旨在探讨PVN AT 1a在升高Ang-II的炎症和交感神经兴奋作用中的作用。所提出的实验将检验以下总体假设：Ang-II作用于PVN AT 1a受体以增强炎症和小胶质细胞活化，并且这是Ang-II诱导的高血压和增强的交感神经流出的重要机制。在第一个特定目的中，实验将利用小鼠中的Cre/lox系统来测试PVN AT 1a对于Ang-II诱导的血压和交感神经系统活动增加是必需的这一特定假设。将在PVN中缺乏AT 1a的小鼠和对照组中评估血管紧张素II诱导的心血管功能障碍（远程血压评估）和大脑心血管控制中心的神经元激活（c-Fos免疫组织化学）。在第二个具体目标中，Cre/lox系统和药理学方法在小鼠中的组合将用于确定PVN AT 1a、转化生长因子β和炎症之间的相互作用在Ang-II升高期间调节心血管功能中的作用。具体而言，将评估PVN AT 1a和转化生长因子β信号传导对Ang-II升高的炎症和高血压后果的必要性。目标2的重要终点将包括评估PVN和其他心血管控制中心内的促炎细胞因子和小胶质细胞活化，以及心血管功能的遥测评估。这项研究具有重要意义，因为揭示Ang-II调节炎症和心血管功能的机制可能会为治疗和预防神经源性高血压提供新的策略。 公共卫生相关性：虽然有许多高血压的治疗策略，但只有不到50%的高血压患者病情得到控制。这项研究的目的是通过研究血管紧张素II在大脑中的炎症作用与高血压之间的相互作用来了解导致高血压的机制。这与公共卫生特别相关，因为揭示Ang-II调节炎症和心血管功能的机制可能会导致治疗和预防高血压的新策略。

DESCRIPTION (provided by applicant): Hypertension is an epidemic health concern and a major risk factor for cardiovascular disease, the leading cause of death in the U.S. Many forms of hypertension are of neurogenic origin; however, the neural mechanism(s) underlying the development and progression of neurogenic hypertension are incompletely understood. Angiotensin-II (Ang-II), the effector peptide of the renin-angiotensin system, is a potent mediator of cardiovascular function that has pleiotropic actions within the brain. Ang-II is known to induce inflammation via the activation of the angiotensin type 1a receptor (AT1a) in a number of peripheral tissues and in the brain and this is thought to contribute to its hypertensive actions. Consistent with this, hypertension, in addition to being accompanied by enhanced renin-angiotensin system activity is also associated with a mild inflammatory state. One critical site of Ang-II actions within the brain is the paraventricular nucleus of the hypothalamus (PVN), which densely expresses AT1a and integrates signals to and from brain regions critical for the regulation of cardiovascular function and sympathetic nerve activity. This proposal investigates the role of the PVN AT1a in the inflammatory and sympathoexcitatory actions of elevated Ang-II. The proposed experiments will test the overall hypothesis that Ang-II acts at the PVN AT1a receptor to enhance inflammation and microglial activation and that this is an important mechanism for Ang-II-induced hypertension and augmented sympathetic outflow. In the first Specific Aim, experiments will utilize the Cre/lox system in mice to test the specific hypothesis that PVN AT1a are necessary for Ang-II-induced increases in blood pressure and sympathetic nervous system activity. Angiotensin-II-induced cardiovascular dysfunction (telemetric blood pressure assessment) and neuronal activation (c-Fos immunohistochemistry) of cardiovascular control centers of the brain will be assessed in mice that lack AT1a in the PVN and controls. In the second Specific Aim, a combination of the Cre/lox system and pharmacological approaches in mice will be used to determine the role of interactions between PVN AT1a, transforming growth factor beta and inflammation in the regulation of cardiovascular function during elevated Ang-II. Specifically, the necessity of PVN AT1a and transforming growth factor beta signaling for the inflammatory and hypertensive consequences of elevated Ang-II will be assessed. Important endpoints for Aim 2 will include the assessment of proinflammatory cytokines and microglial activation within the PVN and other cardiovascular control centers, as well as the telemetric assessment of cardiovascular function. The proposed research is significant because uncovering the mechanisms of Ang-II regulation of inflammation and cardiovascular function may lead to new strategies for the treatment and prevention of neurogenic hypertension. PUBLIC HEALTH RELEVANCE: Although there are a number of treatment strategies for high blood pressure, less than 50% of hypertensive patients have their condition under control. The objective of the proposed research is to understand mechanisms contributing to hypertension by investigating interactions between angiotensin-II's inflammatory actions in the brain and high blood pressure. This is of particular relevance to public health because uncovering the mechanisms of Ang-II regulation of inflammation and cardiovascular function may lead to new strategies for the treatment and prevention of hypertension.