FMRI Studies of Cerebrovascular Structure and Function in Low-Renin Hypertension

低肾素高血压脑血管结构和功能的 FMRI 研究

• 批准号: 9147031
• 负责人: Christopher Paul Pawela
• 金额: $ 46.93万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2018-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9147031
• 关键词: Accounting; Adult; Affect; African American; Alleles; American; Angiotensin II; Angiotensins; Animal Model; Biological Availability; Biological Markers; Blood Pressure; Blood Vessels; Blood Volume; Blood flow; Brain; Bypass; Carbon Dioxide; Cataloging; Catalogs; Cerebrovascular Circulation; Cerebrum; Characteristics; Chromosomes; Chromosomes, Human, Pair 13; Chronic; Clinical Research; Consomic Strain; Consumption; Contrast Media; Coupling; Dahl Hypertensive Rats; Data; Dementia; Diet; Disease; Early identification; Electrophysiology (science); Endothelium; Environment; Exhibits; Free Radicals; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Genetic; Goals; Health; Homeostasis; Human; Hypercapnia; Hypertension; Image; Impaired cognition; Impairment; Ischemic Stroke; Knowledge; Lead; Link; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Methodology; Methods; Modeling; Neurons; Nitric Oxide; Norway; Oxidative Stress; Patients; Phenotype; Physiological; Plasma; Preparation; Process; Rat Strains; Rattus; Rattus norvegicus; Renin; Renin-Angiotensin System; Research; Resistance; Risk; Risk Factors; Rodent; Scanning; Sensory; Signal Transduction; Sodium Chloride; Stimulus; Stroke; Structure; System; Testing; Time; United States; Variant; Vascular Dementia; Vasodilation; Work; base; blood oxygen level dependent; cerebrovascular; congenic; consomic; feeding; hemodynamics; imaging biomarker; imaging modality; low renin hypertension; neuroimaging; neurovascular unit; normotensive; relating to nervous system; research study; response; salt sensitive; salt sensitive hypertension

 DESCRIPTION (provided by applicant): Hypertension is the quintessential multisystem disease and is influenced by a wide range of factors including genetics and the environment. Chronic hypertension causes reduced vascular function, reduced blood flow, damaged cerebral autoregulation, and is a known risk factor for ischemic stroke and vascular-associated cognitive decline. Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is sensitive to changes in cerebrovascular hemodynamic function. Strong preliminary rodent fMRI data demonstrate a diminished cerebrovascular BOLD hyperemic response to forepaw sensory stimulation in salt- induced hypertensive Dahl Salt-Sensitive (SS) rats, a widely-used animal model of low-renin hypertension. Clinically, salt-induced low-renin hypertension accounts for 25% of all essential hypertensive patients, but 75% in African Americans. Additional fMRI experiments revealed an earlier and increased cerebral hemodynamic response to vasodilation by CO2 challenge in hypertensive SS rats. Our data suggests that neurovascular coupling is impaired in low-renin salt-induced hypertension since the diminished BOLD response is neuronal in origin and CO2 acts directly on the vasculature bypassing the neurovascular unit. Mechanistically, we hypothesize that salt-sensitive hypertension leads to vessel endothelium dysfunction through damage by oxidative stress. Free radicals reduce the bioavailability of nitric oxide, a key factor in neurovascular coupling. Our hypothesis is based on our previous work in isolated blood vessels of hypertensive SS rats. We have also shown in isolated vessel preparations that these hypertensive vascular phenotypes are associated with the SS Renin allele. Our proposed research plan has three goals: 1) Characterize the neurovascular uncoupling in salt-induced hypertension. 2) Define the sensitivity and selectivity of the brain BOLD fMRI signal to chronic hypertension. 3) Determine the influence of the SS Renin gene allele on phenotypic differences in the BOLD signal in salt-induced hypertension. These goals will be pursued in three Specific Aims. Aim 1: we will simultaneously measure evoked neural activity and BOLD fMRI response in SS and in Brown Norway salt- resistant normotensive rats. Aim 2: we will relate BOLD signal characteristics (e.g. intensity) and physiological factors (e.g. cerebral blood volume) to salt-induced hypertension. Aim 3: we will examine the influence of the Renin gene on the phenotypic variation in BOLD signal in genetically modified rat strains under both low and high-salt consumption. This project will build a platform methodology for resolving the influence of vascular genes on the BOLD signal and lead to potential BOLD fMRI biomarkers for hypertensive cerebral blood flow changes that precede ischemic stroke. Since hypertension affects 1 of every 3 Americans, this work will additionally impact interpretation of human fMRI exams.

 描述（由申请人提供）：高血压是典型的多系统疾病，受到包括遗传和环境在内的多种因素的影响，慢性高血压会导致血管功能下降、血流量减少、大脑自动调节受损，并且是已知的危险因素。缺血性中风和血管相关的认知能力下降（BOLD）功能磁共振成像（fMRI）对脑血管血流动力学功能的变化很敏感。研究表明，盐诱导的高血压 Dahl 盐敏感 (SS) 大鼠对前爪感觉刺激的脑血管 BOLD 充血反应减弱，SS 是一种广泛使用的低肾素高血压动物模型。临床上，盐诱导的低肾素高血压占 25%。的所有原发性高血压患者中，但非裔美国人中的 75％ 额外的功能磁共振成像实验显示，高血压 SS 大鼠对 CO2 刺激引起的血管舒张的脑血流动力学反应较早且增加。表明低肾素盐诱导的高血压中神经血管耦合受损，因为 BOLD 反应减弱是神经元起源的，而 CO2 绕过神经血管单元直接作用于脉管系统，从机制上讲，我们发现盐敏感性高血压通过以下方式导致血管内皮功能障碍。氧化应激造成的损伤会降低一氧化氮的生物利用度，而一氧化氮是神经血管耦合的关键因素。我们的假设是基于我们之前对高血压 SS 大鼠的离体血管的研究。我们还在分离的血管制剂中表明，这些高血压血管表型与 SS 肾素等位基因相关。我们提出的研究计划有三个目标：1）表征盐诱导高血压的神经血管解偶联。大脑 BOLD fMRI 信号对慢性高血压的影响 3) 确定 SS 肾素基因等位基因对盐诱发高血压中 BOLD 信号表型差异的影响 这些目标将在三个具体目标中实现。目标 1：我们将同时测量 SS 和挪威耐盐正常血压大鼠的诱发神经活动和 BOLD fMRI 反应。 目标 2：我们将 BOLD 信号特征（例如强度）和生理因素（例如脑血量）联系起来。目标 3：我们将研究肾素基因对低盐和高盐消耗下转基因大鼠品系中 BOLD 信号表型变异的影响。该项目将建立一个平台方法来解决血管基因对 BOLD 信号的影响，并为缺血性中风之前的高血压脑血流变化提供潜在的 BOLD fMRI 生物标志物，因为高血压影响着每 3 个美国人中的 1 个，这项工作还将产生额外的影响。人类功能磁共振成像检查的解释。