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The Role of the Hippocampal Vasculature in Vascular Cognitive Impairment and Dementia

海马脉管系统在血管性认知障碍和痴呆中的作用

基本信息

批准号：
10448595
负责人：
Abbie C Chapman
金额：
$ 49.76万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10448595
关键词：
Adult Affect Age Age-Months Aging Angiotensins Atrophic Blood Vessels Blood capillaries Blood flow Brain Brain Hypoxia-Ischemia Brain region Buffers Cerebrovascular Disorders Cerebrum Chronic Clinical Research Cognition Cognitive Cognitive aging Data Dementia Endothelin-1 Endothelium Female Functional disorder Goals Health Hippocampus (Brain)Hypertension Impaired cognition Impairment In Vitro Inbred SHR Rats Individual Injury Knowledge Learning Lesion Measures Mediator of activation protein Memory Memory Loss Memory impairment Metabolic Microcirculation Modeling Muscle function Nature Neurocognitive Neuronal Injury Neuronal Plasticity Neurons Outcome Study Oxidative Stress Oxidative Stress Pathway Pathogenesis Pathologic Pathway interactions Patients Perfusion Persons Pharmacology Population Postmenopause Property Publishing Rattus Rest Risk Risk Factors Role Serum Sex Differences Signal Transduction Structure TNF gene Therapeutic Vascular Cognitive Impairment Vascular Dementia Vascular Smooth Muscle Vasoconstrictor Agents Vasodilation arteriole cerebral microvasculature cerebrovascular cerebrovascular pathology density disability endothelial dysfunction healthy aging hemodynamics hippocampal atrophy hypertensive hypoperfusion hypoxic ischemic injury improved in vivo male middle age neurovascular neurovascular coupling new therapeutic target normal aging normotensive novel oxidative damage pressure prevent response sex vascular cognitive impairment and dementia white matter

项目摘要

Chronic hypertension affects over 100 million adults in the US and is a major risk factor for cerebrovascular disease and vascular cognitive impairment (VCI). VCI involves impairment in multiple cognitive domains, often affecting the hippocampus and memory function leading to dementia. The hippocampus is a deep brain structure that is central to learning and memory and particularly susceptible to injury. Perfusion of the hippocampus is maintained by small hippocampal arterioles (HAs) that are critical to both basal- and activity-dependent changes in blood flow. Cognitive decline occurs more rapidly in the setting of chronic hypertension compared to normal aging; however, how chronic hypertension and aging affect HAs remains unclear and could contribute to VCI. The goal of this proposal is to investigate the novel role of HAs in healthy cognitive aging and VCI associated with chronic hypertension. Our preliminary and published data show that HAs were hyperconstricted and had impaired vasodilatory function in a rat model of chronic hypertension. Further, hippocampal perfusion was significantly reduced and memory impaired during chronic hypertension that occurred as a function of age. Importantly, HA dysfunction preceded these changes in perfusion and memory function, suggesting hypertension-induced memory decline is vascular in nature. Our central hypothesis is that chronic hypertension progressively decreases the vasodilatory function of HAs that reduces resting and activity-dependent changes in hippocampal perfusion, resulting in neuronal injury and VCI. Aim 1 will investigate HA endothelial and vascular smooth muscle function, including vasoconstrictive and vasodilatory pathways, in normotensive and hypertensive rats by studying isolated and pressurized HAs in vitro. Circulating potent vasoconstrictors (e.g. angiotensin II, endothelin-1, tumor necrosis factor alpha) that are elevated during chronic hypertension and cause oxidative stress and damage endothelium will be investigated as underlying mechanisms by which chronic hypertension causes hyperconstriction and impaired vasodilation of HAs. Aim 2 will investigate progressive changes in hippocampal perfusion and neurovascular coupling – the innate ability of the brain to increase local blood flow in response to neuronal activity – as it relates to neuronal function and memory in normotensive and hypertensive rats across the lifetime. We will determine the role of HAs in age- and hypertension-induced changes in hippocampal hemodynamics by investigating if therapeutically improving HA function prevents perfusion deficits, protects hippocampal neurons and slows cognitive decline to be similar to normal aging. This proposal will use both male and post-menopausal female rats to investigate sex differences in hypertension- induced HA dysfunction, and whether one sex is more susceptible to age- or hypertension-induced changes in hippocampal neurovascular function. The outcome of these studies will provide an understanding of the involvement of the hippocampal vasculature in memory decline associated with normal aging, and how this may be accelerated during chronic hypertension and contribute to VCI.