Angiotensin-(1-7) and Hypothalamic control of blood pressure

血管紧张素-(1-7) 和下丘脑对血压的控制

• 批准号: 10593133
• 负责人: Amy Christine Arnold
• 金额: $ 44.99万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593133
• 关键词: Acute; Animals; Attenuated; Bathing; Blood Pressure; Brain; Brain region; Cardiovascular system; Cells; Chronic; Cyclic AMP; Data; Dependence; Dependovirus; Electrophysiology (science); Enzymes; Epidemic; Exhibits; Female; Gene Expression; Genetic; Glutamates; Green Fluorescent Proteins; High Fat Diet; Hormones; Hypertension; Hypothalamic structure; Immunohistochemistry; Kidney; Knockout Mice; Laboratories; Leptin; Link; Measures; Methods; Modeling; Mus; Nerve; Neurons; Neurotransmitters; Obese Mice; Obesity; Obesity Related Hypertension; Organ; Pathway interactions; Peripheral; Phenotype; Physiological; Pro-Opiomelanocortin; Publishing; Renin-Angiotensin System; Reporter; Research; Risk; Second Messenger Systems; Structure of nucleus infundibularis hypothalami; Sympathetic Nervous System; Synapses; Technology; Testing; Time; Transgenic Mice; angiotensin I (1-7); antagonist; blood pressure control; blood pressure elevation; blood pressure reduction; conditional knockout; diet-induced obesity; gamma-Aminobutyric Acid; genetic approach; global health; in vivo; insight; male; melanocyte; mouse model; neural circuit; neurobiotin; novel; novel strategies; obesity treatment; paraventricular nucleus; patch clamp; pharmacologic; prevent; receptor; response; restoration; sex; vascular bed

PROJECT SUMMARY Obesity is a global epidemic that is associated with excessive central sympathetic outflow to cardiovascular end organs to elevate blood pressure and predispose to hypertension. Accumulating evidence from our laboratory suggests that deficiency of angiotensin-(1-7), a protective hormone of the renin-angiotensin system, provides an important link connecting obesity with sympathetic overactivation and hypertension. Our published observations, combined with preliminary data, support this concept by showing that high fat diet-induced obese mice exhibit circulating angiotensin-(1-7) deficiency, and restoration of this hormone attenuates cardiovascular sympathetic overactivity and hypertension in this model. Our preliminary data expand on these phenotypic findings by providing evidence that angiotensin-(1-7) depressor effects require activation of neural circuits originating in the arcuate nucleus of the hypothalamus (ARC). We show that both systemic and intra-ARC angiotensin-(1-7) lowers blood pressure in mice, with effects prevented by deletion of angiotensin-(1-7) mas receptors in the ARC. We further show that blood pressure lowering effects of angiotensin-(1-7) require activation of specific subpopulations of ARC neurons that are likely proopiomelanocortin (POMC)-expressing, as well as cyclic AMP second messenger systems. We propose that angiotensin-(1-7) selectively activates POMC neurons that release the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). In support of this, we show that: mas receptors are highly localized to GABAergic POMC neurons; and angiotensin-(1-7) increases GABA synthesis enzymes in the ARC without altering POMC gene expression. Based on these data, this proposal will test the central hypothesis that angiotensin-(1-7) activates mas receptors on GABAergic POMC neurons in the ARC to reduce cardiovascular sympathetic outflow and lower blood pressure. Aim 1 will determine if angiotensin-(1-7) selectively increases the excitability of GABAergic ARC POMC neurons using transgenic mouse reporter lines combined with whole cell patch clamp electrophysiology methods. Aim 2 will determine if angiotensin-(1-7) requires mas receptors in ARC POMC neurons to lower blood pressure via GABA release mechanisms using a novel mas receptor conditional knockout mouse model we developed and chemogenetic and pharmacological approaches. Aim 3 will determine if angiotensin-(1-7) decreases sympathetic nerve traffic to cardiovascular organs using sophisticated in vivo isolated nerve recording approaches. These studies will be conducted in male and female mice under control and high fat diet conditions, to determine the impact of sex and obesity on angiotensin-(1-7) activation of this neural circuit. Overall, this proposal will span the cellular to whole animal levels to provide new insight into angiotensin-(1-7) effects on neural circuits controlling sympathetic outflow and blood pressure, and related cellular and neurotransmitter mechanisms. Importantly, these studies have more long-term potential to determine if targeting angiotensin-(1-7) represents a novel approach for the treatment of obesity-related hypertension.

项目摘要 肥胖是一种全球流行病，与心血管的过度交感神经相关 结束器官升高血压并易于高血压。积累我们的证据 实验室表明，血管紧张素 - （1-7）的缺乏，肾素 - 血管紧张素系统的保护性激素， 提供了一个重要的联系，将肥胖与交感神经过度激活和高血压联系起来。我们出版了 观察结果与初步数据相结合，通过表明高脂饮食引起的肥胖来支持这一概念 小鼠表现出循环血管紧张素 - （1-7）缺乏，并恢复这种激素的心血管 该模型中的交感性过度活动和高血压。我们的初步数据扩展了这些表型 通过提供的证据表明血管紧张素 - （1-7）抑制剂效应需要激活神经回路 起源于下丘脑（ARC）的弧形核。我们证明了全身和弧内的 血管紧张素 - （1-7）降低小鼠的血压，并通过血管紧张素（1-7）MAS的缺失阻止效果 弧中的受体。我们进一步表明血压降低血管紧张素的作用 - （1-7）需要 激活可能是促蛋白酶素（POMC）表达的电弧神经元的特定亚群 以及循环AMP第二信使系统。我们提出血管紧张素 - （1-7）有选择地激活 释放抑制性神经递质γ-氨基丁酸（GABA）的POMC神经元。支持 这是我们表明的：MAS受体高度局限于GABA能POMC神经元；和血管紧张素 - （1-7） 在不改变POMC基因表达的情况下增加了ARC中的GABA合成酶。基于这些数据， 该提案将检验中心假设，即血管紧张素（1-7）激活MAS受体在Gabaergic上 ARC中的POMC神经元可减少心血管交感神经流出并降低血压。目标1意志 确定使用血管紧张素（1-7）选择性地提高使用GABA能弧神经元的兴奋性 转基因小鼠报告基因与全细胞斑块夹电生理方法结合使用。 AIM 2意志 确定血管紧张素 - （1-7）是否需要ARC POMC神经元中的MAS受体通过 GABA释放机制使用新型MAS受体条件敲除小鼠模型，我们开发了 化学和药理学方法。 AIM 3将确定血管紧张素 - （1-7）是否降低 使用复杂的体内神经记录，与心血管器官的交感神经交通 方法。这些研究将在控制和高脂饮食的雄性和雌性小鼠中进行 条件，确定性别和肥胖对这种神经回路激活血管紧张素（1-7）的影响。 总体而言，该建议将跨越细胞到整个动物水平，以提供对血管紧张素的新见解 - （1-7） 对控制交感神经流出和血压的神经回路的影响，以及相关的细胞和 神经递质机制。重要的是，这些研究具有更大的长期潜力来确定是否是否 靶向血管紧张素（1-7）代表了一种治疗与肥胖相关高血压的新方法。