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: 10381736
• 负责人: Amy Christine Arnold
• 金额: $ 45.48万
• 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/10381736
• 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; Glutamates; Green Fluorescent Proteins; High Fat Diet; Hormones; Hypertension; Hypothalamic structure; Immunohistochemistry; Kidney; Laboratories; Leptin; Link; Measures; Methods; Modeling; Mus; Nerve; Neurons; Neurotransmitters; Obese Mice; Obesity; Obesity Related Hypertension; Organ; Pathway interactions; Peripheral; Pharmacology; 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; base; blood pressure control; blood pressure elevation; blood pressure reduction; conditional knockout; diet-induced obesity; gamma-Aminobutyric Acid; global health; in vivo; insight; male; melanocyte; mouse model; neural circuit; neurobiotin; novel; novel strategies; obesity treatment; paraventricular nucleus; patch clamp; 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.

项目总结 肥胖是一种全球流行病，与过度的中枢交感神经流出到心血管有关 末梢器官使血压升高，易患高血压。从我们的证据中积累证据 实验室提示，肾素-血管紧张素系统的保护性激素血管紧张素-(1-7)缺乏， 提供了联系肥胖和交感神经过度激活和高血压的重要纽带。我们出版的 结合初步数据，观察结果表明，高脂肪饮食会导致肥胖，从而支持这一观点 小鼠表现出循环血管紧张素-(1-7)缺乏，恢复这种激素会减弱心血管疾病 在这个模型中交感神经过度活动和高血压。我们的初步数据对这些表型进行了扩展 通过提供证据发现血管紧张素-(1-7)降压效应需要激活神经回路 起源于下丘脑的弓状核(ARC)。我们表明，无论是系统性的还是ARC内部的 血管紧张素-(1-7)可降低小鼠血压，其作用可被血管紧张素-(1-7)mAs的缺失所阻止 ARC中的受体。我们进一步表明，血管紧张素-(1-7)的降压作用需要 激活可能表达前阿片黑素皮质素(POMC)的ARC神经元的特定亚群， 以及环状AMP第二信使系统。我们认为血管紧张素-(1-7)选择性地激活 释放抑制性神经递质γ-氨基丁酸(GABA)的POMC神经元。为了支持…… 这表明：MAS受体高度定位于GABA能POMC神经元；血管紧张素-(1-7) 在不改变POMC基因表达的情况下，增加ARC中的GABA合成酶。根据这些数据， 这一提议将检验中心假设，即血管紧张素-(1-7)激活GABA能上的MAS受体。 ARC中的POMC神经元可减少心血管交感神经流出，降低血压。目标1将 血管紧张素-(1-7)是否选择性地增加GABA能ARC POMC神经元的兴奋性 转基因小鼠报告系结合全细胞膜片钳电生理方法。目标2将 确定血管紧张素-(1-7)是否需要ARC POMC神经元上的MAS受体通过 使用我们开发的一种新的MAS受体条件性基因敲除小鼠模型的GABA释放机制 化学遗传学和药理学方法。目标3将确定血管紧张素-(1-7)是否降低 使用复杂的在体分离神经记录向心血管器官的交感神经交通 接近了。这些研究将在对照和高脂肪饮食的雄性和雌性小鼠身上进行 以确定性别和肥胖对血管紧张素-(1-7)激活这一神经回路的影响。 总体而言，这项提议将跨越细胞水平到整个动物水平，以提供对血管紧张素-(1-7)的新见解。 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，这些研究有更长期的潜力来确定 靶向血管紧张素-(1-7)是治疗肥胖相关高血压的一种新方法。