Interrogating distinct angiotensin type-1 and type-2 receptor containing brain circuits to understand and alleviate hypertension

研究含有不同血管紧张素 1 型和 2 型受体的脑回路以了解和缓解高血压

• 批准号: 10978086
• 负责人: Annette Diane de Kloet
• 金额: $ 22.56万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10978086
• 关键词: Interrogating; distinct; angiotensin; type; receptor

Project Summary Hypertension is a widespread health problem and a major risk factor for cardiovascular disease. Nearly one- third of hypertensive patients suffer from drug-resistant hypertension; a condition associated with activation of brain angiotensin receptors, enhanced sympathetic nervous system activity and elevated levels of circulating vasopressin. The proposed experiments aim to identify neurons within the brain whose excitation or inhibition is coupled to the pathophysiology underlying resistant hypertension. Our preliminary studies using mice with Cre recombinase or green fluorescent protein directed by the genes for the angiotensin type 1a or type 2 receptors (AT1R or AT2R) have provided intriguing insight. We have discovered that neurons in the organum vasculosum of the lamina terminalis (OVLT) and median preoptic nucleus (MnPO) express AT1R or AT2R and send dense excitatory projections to the paraventricular nucleus of the hypothalamus (PVN) and peri-PVN area, respectively. Fascinatingly, optogenetic excitation of such AT1R neurons elicits robust (>40 mmHg) and sustained increases in blood pressure, suggestive of sympathoexcitation and augmented vasopressin secretion. Within the MnPO/OVLT the vast majority of AT2R(s) are NOT expressed on neurons that also synthesize AT1R, but rather, are a separate population of neurons whose excitation may oppose the onset of hypertension. Consistent with this interpretation, we recently discovered that pharmacological activation of AT2R facilitates GABAergic mediated inhibition of vasopressin neurons and reduces systemic vasopressin and blood pressure. We have developed the overall hypothesis that neurons within the MnPO/OVLT that express AT1R or AT2R project to the PVN and peri-PVN area to coordinate sympathetic outflow and vasopressin secretion, and that the relative activities of these neurons predict resistance or susceptibility to hypertension. To address this hypothesis, the proposed studies combine Cre-LoxP technology, in vitro/in vivo optogenetics and classical systems physiology with a mouse model of hypertension. Aim 1 will use optogenetics to probe the connection between neurons in the MnPO/OVLT that express AT1R or AT2R and neurons in the PVN that express vasopressin. Sufficiency and/or necessity of these connections will be determined for the increased sympathetic nervous system activity and vasopressin secretion that promote neurogenic hypertension. Then, Aim 2 will use the Cre-loxP system to delete AT1R and/or AT2R within the MnPO/OVLT and determine whether AT1R/AT2R signaling within these brain nuclei contribute to the etiology of hypertension. Collectively, these experiments will determine whether excitability and/or AT1R/AT2R signaling within this neural circuit can be altered to prevent high blood pressure. These studies have the potential to uncover, at a detailed and mechanistic level, the neural circuits that are compromised during hypertension and, in the long-term, may inform a therapeutic strategy that optimally targets excitation of AT1R- and AT2R-containing neurons to relieve hypertension.

项目摘要 高血压是一个普遍的健康问题，也是心血管疾病的主要危险因素。将近一个 三分之一的高血压患者患有耐药性高血压；与激活相关的条件 脑血管紧张素受体，增强的交感神经系统活动和循环水平升高 加压素。提出的实验旨在识别大脑中的神经元的激发或抑制作用 与耐药性高血压的病理生理学结合。我们使用CRE小鼠的初步研究 由血管紧张素1A型或2型受体的基因引导的重组酶或绿色荧光蛋白 （AT1R或AT2R）提供了有趣的见解。我们已经发现有组织血管中的神经元 lamina末端（OVLT）​​和中位前核（MNPO）表达AT1R或AT2R的中位数，并发送致密 分别对下丘脑（PVN）和Peri-PVN区域的室室核的兴奋性预测。 令人着迷的是，这种AT1R神经元的光遗传激发会引起鲁棒（> 40 mmHg），并且持续增加 在血压中，提示交感神经和增强的加压素分泌。在 MNPO/OVLT绝大多数AT2R（S）并未在合成AT1R的神经元上表达 是单独的神经元种群，其激发可能会反对高血压发作。与 这种解释，我们最近发现AT2R的药理激活有助于GABA能 介导的加压素神经元抑制并降低了全身加压素和血压。我们有 开发了总体假设，即MNPO/OVLT中的神经元表达AT1R或AT2R项目的神经元 PVN和PERI-PVN区域以协调交感神经流出和加压素分泌，并且相对 这些神经元的活性预测了高血压的抵抗力或易感性。为了解决这一假设， 拟议的研究结合了Cre-loxp技术，体外/体内光遗传学和经典系统生理学 用小鼠高血压模型。 AIM 1将使用光遗传学探测神经元之间的连接 表达加压素的PVN中表达AT1R或AT2R的MNPO/OVLT。足够 和/或这些连接的必要性将确定增加的交感神经系统活动 和加压素分泌，促进神经源性高血压。然后，AIM 2将使用Cre-loxp系统 删除MNPO/OVLT内的AT1R和/或AT2R 脑核有助于高血压的病因。总的来说，这些实验将确定是否 可以改变该神经回路内的兴奋性和/或AT1R/AT2R信号传导，以防止高血压。 这些研究有可能在详细且机械水平上揭示的神经回路 在高血压期间受到妥协，从长远来看，可能会告知一种最佳针对的治疗策略 含有AT1R和AT2R的神经元的激发以减轻高血压。