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: 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
• 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

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，是脑血管病的主要危险因素 疾病和血管性认知障碍（VCI）。 VCI 涉及多个认知领域的损伤，通常 影响海马体和记忆功能，导致痴呆。海马体是大脑深层结构 这是学习和记忆的核心，特别容易受伤。海马体的灌注是 由海马小动脉 (HA) 维持，这对于基础和活动依赖性变化都至关重要 在血液流动中。与正常人相比，慢性高血压患者的认知能力下降更快 老化;然而，慢性高血压和衰老如何影响 HA 并可能导致 VCI 仍不清楚。 该提案的目标是研究 HA 在健康认知衰老和 VCI 相关中的新作用 患有慢性高血压。我们的初步和公布的数据表明，HA 是超收缩的，并且具有 慢性高血压大鼠模型中血管舒张功能受损。此外，海马灌注 随着年龄的增长，慢性高血压期间记忆力显着下降和记忆力受损。 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 高血压引起的记忆力下降本质上是血管性的。我们的中心假设是慢性高血压 逐渐降低 HA 的血管舒张功能，从而减少静息和活动依赖性变化 海马灌注，导致神经元损伤和 VCI。目标 1 将研究 HA 内皮和血管 平滑肌功能，包括血管收缩和血管舒张途径，在正常血压和 通过在体外研究分离和加压的 HA 来治疗高血压大鼠。循环强效血管收缩剂（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 引起氧化应激和损伤内皮细胞的潜在机制将被研究作为慢性 高血压会导致HA过度收缩和血管舒张受损。目标 2 将调查渐进式 海马灌注和神经血管耦合的变化——大脑增加局部能力的先天能力 血流对神经元活动的反应——因为它与正常血压和血压状态下的神经元功能和记忆有关 高血压大鼠的一生。我们将确定 HA 在年龄和高血压诱发的疾病中的作用 通过研究治疗性改善 HA 功能是否可以预防海马血流动力学的变化 灌注不足，保护海马神经元并减缓认知能力下降，使其与正常衰老相似。这 该提案将使用雄性和绝经后雌性大鼠来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引起的 HA 功能变化的影响 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相关的记忆衰退，以及这如何可能 慢性高血压期间会加速并导致 VCI。