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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

基本信息

批准号：
10523047
负责人：
Annette Diane de Kloet
金额：
$ 15万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10523047
关键词：
Address Angiotensin II Angiotensin Receptor Angiotensins Antihypertensive Agents Area Blood Pressure Brain Cardiovascular Diseases Cardiovascular system Cause of Death Cell Nucleus Cells Consumption Coupled Cre lox recombination system Cre-LoxP Desire for food Development Drug resistance Endocrine Enterobacteria phage P1 Cre recombinase Equilibrium Etiology Experimental Models Functional disorder Gene Transfer Genes Genetic Recombination Glutamates Goals Green Fluorescent Proteins Health Heart Hypertension Hypothalamic structure In Vitro Liquid substance Mediating Mus Neurons Neurosecretory Systems Pathogenesis Patients Physiology Population Predisposition Receptor Inhibition Receptor Signaling Receptor, Angiotensin, Type 1 Reporter Genes Research Resistance Resistant Hypertension Role Signal Transduction Sodium Chloride Stimulus Sympathetic Nervous System Synapses System Technology Testing Therapeutic Thirst Type 2 Angiotensin II Receptor United States Vasopressins Viral blood pressure control blood pressure elevation blood pressure reduction blood pressure regulation cardiovascular risk factor clinically relevant experimental study extracellular fascinate hypertensive in vivo insight magnocellular mouse model neural neural circuit neurogenic hypertension neuronal excitability neuroregulation neurotransmission novel optogenetics organum vasculosum of the lamina terminalis paraventricular nucleus pharmacologic phenotypic biomarker preoptic nucleus prevent receptor resilience response vasoconstriction

项目摘要

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;一种与激活脑血管紧张素受体，增强交感神经系统活动和循环水平升高加压素拟议的实验旨在确定大脑中的神经元，其兴奋或抑制与顽固性高血压的病理生理学有关。我们的初步研究使用Cre小鼠重组酶或绿色荧光蛋白，由血管紧张素1a型或2型受体的基因指导 (AT1R或者AT 2 R）提供了有趣的见解。我们发现血管器中的神经元终板和正中视前核表达AT 1 R或AT 2 R，分别向下丘脑室旁核（PVN）和PVN周围区的兴奋性投射。令人着迷的是，这种AT 1 R神经元的光遗传学激发产生了稳健的（>40 mmHg）和持续的增加在血压方面，提示交感神经兴奋和加压素分泌增加。内 MnPO/OVLT绝大多数AT 2 R在也合成AT 1 R的神经元上不表达，而是，是一个单独的神经元群体，其兴奋可能对抗高血压的发作。符合根据这种解释，我们最近发现AT 2 R的药理学激活促进GABA能介导的血管加压素神经元抑制和降低全身血管加压素和血压。我们有提出了一个总体假设，即MnPO/OVLT中表达AT 1 R或AT 2 R的神经元投射到室旁核和室旁核周围区协调交感神经流出和加压素分泌，这些神经元的活动预示着对高血压的抵抗力或易感性。为了解决这个假设，提出的研究结合了联合收割机Cre-LoxP技术、体外/体内光遗传学和经典系统生理学一个高血压的老鼠模型。Aim 1将使用光遗传学来探测神经元之间的联系，表达AT 1 R或AT 2 R的MnPO/OVLT和表达加压素的PVN神经元。充分性和/或这些连接的必要性将针对增加的交感神经系统活动来确定和血管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AT 1 R和/或AT 2 R，并确定这些内的AT 1 R/AT 2 R信号传导是否脑核团有助于高血压的病因学。总的来说，这些实验将决定可以改变该神经回路内的兴奋性和/或AT 1 R/AT 2 R信号传导以防止高血压。这些研究有可能揭示，在详细和机械的水平，神经回路，在高血压期间受损，并且从长远来看，可以为最佳靶向治疗策略提供信息。兴奋含AT 1 R和AT 2 R的神经元以缓解高血压。