Neurons expressing angiotensin type 2 receptors in the NTS as an access point for cardiovascular control.

NTS 中表达 2 型血管紧张素受体的神经元作为心血管控制的接入点。

• 批准号: 10082461
• 负责人: Eric Gerald Krause
• 金额: $ 56.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10082461
• 关键词: Acetates; Affect; Agonist; Animal Model; Antihypertensive Agents; Area; Attenuated; Baroreflex; Basic Science; Blood; Blood Pressure; Blood Vessels; Brain; Brain Stem; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Cell Nucleus; Cells; DOCA; Deoxycorticosterone; Development; Diabetes Mellitus; Disease; Enterobacteria phage P1 Cre recombinase; Etiology; GABA Receptor; Gene Transfer; Genetic; Hypertension; In Vitro; Laboratories; Lead; Life Style; Link; Mediating; Mediation; Messenger RNA; Metabolic syndrome; Mus; Nerve; Neurons; Neurosciences; Neurotransmitters; Nucleus solitarius; Obesity; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Pressoreceptors; Proteins; Receptor Activation; Receptor Gene; Receptor Signaling; Reflex control; Reporter; Reporting; Research; Resistance; Resistant Hypertension; Risk Factors; Site; Stroke; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transgenic Mice; Translating; Type 2 Angiotensin II Receptor; Viral; Virus; Work; base; blood pressure reduction; blood pressure regulation; cardiovascular risk factor; experimental study; gamma-Aminobutyric Acid; genetic approach; improved; in vivo; indexing; innovation; mouse model; neurogenic hypertension; neurotransmission; novel; novel strategies; novel therapeutic intervention; novel therapeutics; optogenetics; pre-clinical; receptor; recombinase-mediated cassette exchange; salt sensitive hypertension; synthetic enzyme; therapeutic target; treatment strategy; vasoconstriction

Project Summary Hypertension is the most important risk factor for the development of cardiovascular disease, the leading cause of death in the U.S. Despite therapeutic advancements, nearly 20-30% of hypertensive patients have uncontrolled high blood pressure. This resistant hypertension is associated with elevated sympathetic activity and abnormal baroreflex reflex control and thus is termed neurogenic hypertension. Animal models of neurogenic hypertension consistently implicate augmented release of GABA within the intermediate nucleus of the solitary tract (intNTS) as a contributing pathophysiological mechanism. Correcting this pathophysiological mechanism is a logical step towards decreasing high blood pressure of neurogenic origin. However, GABA and its receptors are poor therapeutic targets because GABA is the predominant inhibitory neurotransmitter in the CNS. To circumvent this impediment we began investigating whether neurons in the intNTS that express angiotensin type 2 receptors (AT2R) may serve as an access point for therapeutic interventions that relieve neurogenic hypertension. Using a novel transgenic mouse model (AT2R-eGFP reporter mouse) we discovered that GABA neurons in the intNTS robustly express AT2R and optogenetic excitation of these neurons significantly increases blood pressure. Intriguingly, DOCA-salt hypertension in mice increased indices of GABA synthesis in the intNTS but central delivery of the AT2R agonist, Compound 21 (C21), abrogated this hypertension and downregulated indices of GABA synthesis in the intNTS. Relevant to the proposed research, the antihypertensive effects of brain AT2R activation were abolished by deleting AT2R from GABA neurons. Based on these results we hypothesize that GABA neurons in the intNTS that express AT2R may be manipulated to reverse the onset of neurogenic hypertension. Two Specific Aims are proposed to substantiate or refute this hypothesis. Aim 1 combines genetic and pharmacological approaches to evaluate the consequences of deleting or stimulating AT2R on GABAergic neurons in the intNTS. Aim 1 tests the hypothesis that activation of AT2R expressed on GABAergic neurons in the intNTS alleviates DOCA-salt hypertension in mice by decreasing GABA synthetic enzymes within these neurons, which consequently decreases sympatho- excitation and improves baroreflex function. Aim 2 utilizes in vitro optogenetic and in vivo chemogenetic approaches to evaluate how DOCA-salt hypertension with or without C21 affects GABA neurotransmission within baroreflex circuits mediating cardiovascular function. Aim 2 tests the hypothesis that the activity of neurons within the intNTS that express AT2R control baroreflex sensitivity and sympathetic outflow and their selective inhibition mediates the reversal of hypertension. Execution of the proposed experiments will identify a discrete population of neurons that can be targeted to control blood pressure and provide preclinical evidence for the development of novel approaches for alleviating resistant hypertension.

项目摘要 高血压是心血管疾病发展的最重要危险因素， 尽管治疗取得了进展，但仍有近20-30%的高血压患者 不受控制的高血压这种顽固性高血压与交感神经活性升高有关 以及异常的压力反射控制，因此被称为神经源性高血压。动物模型 神经源性高血压一贯暗示增强释放GABA的中间核内的 孤束（intNTS）作为一个贡献的病理生理机制。纠正这种病理生理 这一机制是降低神经源性高血压的合理步骤。然而，GABA和 它的受体是不良的治疗靶点，因为GABA是主要的抑制性神经递质， CNS。为了克服这一障碍，我们开始研究intNTS中的神经元是否表达 血管紧张素2型受体（AT 2 R）可作为治疗干预的切入点， 神经性高血压使用一种新的转基因小鼠模型（AT 2 R-eGFP报告小鼠），我们发现 intNTS中的GABA神经元强烈表达AT 2 R和这些神经元的光遗传学兴奋 显著增加血压。有趣的是，DOCA盐高血压小鼠的GABA指数增加 在intNTS中的合成，但是AT 2 R激动剂化合物21（C21）的中枢递送消除了这种情况 高血压和intNTS中GABA合成的下调指标。与拟议的研究有关， 从GABA神经元中删除AT 2 R可消除脑AT 2 R激活的降压作用。 基于这些结果，我们推测，在intNTS中表达AT 2 R的GABA神经元可能是 来逆转神经性高血压的发作提出了两个具体目标， 证实或反驳这一假设。目的1结合遗传学和药理学方法来评估 在intNTS中删除或刺激AT 2 R对GABA能神经元的影响。目标1检验假设 在intNTS中GABA能神经元上表达的AT 2 R的激活证实了DOCA盐高血压， 小鼠通过减少这些神经元内的GABA合成酶，从而减少交感神经功能， 兴奋和改善压力反射功能。目的2利用体外光遗传学和体内化学遗传学 评估DOCA盐高血压伴或不伴C21如何影响GABA神经传递的方法 压力反射回路介导心血管功能。目的2检验神经元的活动 在表达AT 2 R的intNTS内，控制压力反射敏感性和交感神经流出， 抑制介导高血压的逆转。执行拟议的实验将确定一个离散的 可以靶向控制血压的神经元群体，并为血压控制提供临床前证据。 开发缓解顽固性高血压的新方法。