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

 描述(申请人提供)：高血压是典型的多系统疾病，受包括遗传和环境在内的广泛因素的影响。慢性高血压导致血管功能降低、血流量减少、大脑自我调节受损，是缺血性中风和血管相关认知能力下降的已知危险因素。血氧水平依赖(BOLD)功能磁共振成像(FMRI)对脑血管血流动力学功能的变化敏感。强大的啮齿动物fMRI初步数据显示，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大胆充血反应减弱，这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所有原发性高血压患者的25%，但在非裔美国人中占75%。另外的功能磁共振成像实验显示，高血压SS大鼠对二氧化碳刺激的血管扩张反应更早且增强。我们的数据表明，在低肾素盐诱导的高血压中，神经血管偶联受到损害，因为这种减弱的BOLD反应起源于神经元，而二氧化碳直接作用于血管系统，绕过神经血管单位。从机制上讲，我们假设盐敏感型高血压通过氧化应激损伤导致血管内皮功能障碍。自由基降低了一氧化氮的生物利用度，一氧化氮是神经血管偶联的关键因素。我们的假设是基于我们之前在高血压SS大鼠的分离血管中所做的工作。我们还在分离的血管标本中表明，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)表征盐诱导的高血压的神经血管解偶联。2)明确脑BOLD fMRI信号对慢性高血压的敏感性和选择性。3)确定SS肾素基因等位基因对盐诱导高血压BOLD信号表型差异的影响。这些目标将通过三个具体目标来实现。目的1：我们将同时检测SS和Brown挪威耐盐正常血压大鼠的诱发神经活动和BOLD fMRI反应。目的2：我们将BOLD信号特征(如强度)和生理因素(如脑血容量)与盐源性高血压联系起来。目的：研究肾素基因对低盐和高盐摄入下转基因大鼠BOLD信号表型变异的影响。该项目将为解决血管基因对BOLD信号的影响建立一个平台方法学，并导致潜在的BOLD功能磁共振生物标记物用于缺血性中风前高血压脑血流的变化。由于高血压影响每3个美国人中的1个，这项工作还将影响对人类功能磁共振检查的解释。

 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.