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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：
10308699
负责人：
Annette Diane de Kloet
金额：
$ 37.56万
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 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308699
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 Pharmacology Physiology Population Predisposition Receptor Signaling Receptor, Angiotensin, Type 1 Reporter Genes Research Resistance Resistant Hypertension Role Signal Transduction Sodium Chloride Stimulus Suggestion 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 hypertensive in vivo insight magnocellular mouse model neural circuit neurogenic hypertension neuronal excitability neuroregulation neurotransmission novel optogenetics organum vasculosum of the lamina terminalis paraventricular nucleus phenotypic biomarker preoptic nucleus prevent receptor relating to nervous system 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.

项目总结