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

• 批准号: 10596617
• 负责人: Abbie C Chapman
• 金额: $ 46.17万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10596617
• 关键词: Acceleration; Adult; Affect; Age; Age Months; Aging; Angiotensin II; 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; Hypertension; Impaired cognition; Impairment; In Vitro; Inbred SHR Rats; Individual; Infarction; Injury; Knowledge; Learning; Lesion; Measures; Mediator; 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; Population; Postmenopause; Predisposition; 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; improved; in vivo; ischemic injury; male; middle age; neurovascular; neurovascular coupling; new therapeutic target; normal aging; normotensive; novel; oxidative damage; pharmacologic; pressure; prevent; protective pathway; response; sex; vascular cognitive impairment and dementia; white matter

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.

慢性高血压影响美国超过1亿成年人，是脑血管的主要危险因素 疾病和血管认知障碍（VCI）。 VCI涉及多个认知领域的损害，通常 影响海马和记忆功能导致痴呆症。海马是深脑结构 这是学习和记忆的核心，尤其容易受到伤害。海马灌注是 由小型海马小动脉（HAS）维持，这对基本和活动依赖性变化至关重要 在血流中。与正常相比，在慢性高血压的情况下，认知能力下降更快 老化;但是，慢性高血压和衰老影响如何尚不清楚，并可能有助于VCI。 该提案的目的是研究HAS在健康认知衰老和VCI相关的新作用 患有慢性高血压。我们的初步和已发布的数据显示，这些数据已经超出了收缩，并且 慢性高血压大鼠模型中的血管舒张功能受损。此外，海马灌注是 在慢性高血压期间显着降低和记忆障碍，这是年龄的函数。 重要的是，HA功能障碍先于灌注和记忆功能的这些变化，这表明 高血压引起的记忆下降本质上是血管的。我们的中心假设是慢性高血压 逐渐降低具有减少静止和活动依赖性变化的血管舒张功能 在海马灌注中，导致神经元损伤和VCI。 AIM 1将调查HA内皮和血管 平滑肌功能，包括血管收缩和血管舒张途径，在正常的和 高血压大鼠通过研究分离和加压在体外。循环潜在的血管收缩剂（例如 血管紧张素II，内皮素-1，肿瘤坏死因子α）在慢性高血压和 导致氧化应激和损伤内皮将被研究为慢性的潜在机制 高血压会导致HAS的高收缩和血管舒张受损。 AIM 2将调查进步 海马灌注和神经血管耦合的变化 - 大脑的先天能力增加局部 响应神经元活性的血液流动 - 与正常性和正常的神经元功能和记忆有关 高血压大鼠一生。我们将确定HAS在年龄和高血压诱导中的作用 海马血流动力学的变化通过研究是否可以改善HA功能 灌注定义，保护海马神经元并减慢认知能力下降，类似于正常衰老。这 提案将使用男性和绝经后女性大鼠研究高血压的性别差异 - 引起的HA功能障碍，以及一种性别是否更容易受到年龄或高血压诱导的变化的影响 海马神经血管功能。这些研究的结果将提供对 海马脉管系统参与与正常衰老有关的记忆下降，以及如何可能 在慢性高血压期间加速并有助于VCI。