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.
Salt-sensitive low-renin hypertension is a common disease and initiates a longitudinal process that includes degradation of cerebrovascular structure and function by oxidative stress. The following three aims will be carried out in a hypertensive rat model: first, determine if neurovascular coupling is impaired in salt-sensitive hypertension, second, establish if functional magnetic resonance imaging (fMRI) can be used as a biomarker for low-renin hypertension in the brain, third, identify the genetic influence of the Renin gene on the fMRI signal. Hypertension is a major risk factor for stroke and vascular dementia, and this study will provide critical knowledge that may lead to early identification of neurovascular impairment.
