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.

慢性高血压在美国影响着1亿多成年人，是脑血管疾病的主要危险因素 疾病和血管认知障碍(VCI)。VCI涉及多个认知域的损害，通常 影响海马体和记忆功能，导致痴呆。海马体是大脑的深层结构 这是学习和记忆的核心，特别容易受到伤害。海马体的灌流是 由对基础改变和活动依赖改变都至关重要的小海马区小动脉(HAS)维持 在血液流动中。与正常人群相比，慢性高血压患者的认知功能下降更快 衰老；然而，慢性高血压和衰老如何影响尚不清楚，并可能导致VCI。 这项建议的目的是调查HAS在健康认知老化和VCI相关的新角色。 患有慢性高血压。我们的初步和公布的数据显示，已经出现了过度收缩和 慢性高血压大鼠模型的血管扩张功能受损。此外，海马区的血流灌注量 随着年龄的增长，慢性高血压的发病率显著降低，记忆力受损。 重要的是，HA功能障碍先于这些血流和记忆功能的变化，这表明 高血压引起的记忆减退本质上是血管性的。我们的中心假设是慢性高血压 逐渐降低HAS的血管扩张功能，从而减少静息和活动依赖的变化 在海马区灌流，导致神经元损伤和VCI。AIM 1将研究HA内皮和血管 正常血压和正常血压患者的血管收缩和血管扩张通路。 通过对高血压大鼠进行体外分离和加压研究。循环中有效的血管收缩药(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 引起氧化应激和内皮损伤将作为慢性疾病的潜在机制进行研究 高血压会导致血管过度收缩和血管扩张功能受损。目标2将调查进步 海马区血流灌注和神经血管偶联的变化--大脑增加局部的先天能力 血流对神经元活动的反应--因为它与正常血压和记忆的神经元功能和记忆有关 终生高血压大鼠。我们将确定HAS在年龄和高血压诱导中的作用 通过研究通过治疗改善HA功能是否可以防止 灌流不足，保护海马神经元，延缓认知衰退，与正常衰老相似。这 该提案将同时使用雄性和绝经后雌性大鼠来研究高血压的性别差异。 诱导的HA功能障碍，以及是否一种性别更容易受到年龄或高血压诱导的 海马神经血管功能。这些研究的结果将使我们了解 在与正常衰老相关的记忆衰退中，海马体血管系统的参与，以及这如何可能 在慢性高血压期间加速，并有助于VCI。