Endothelial Mechanism of Vascular Cognitive Impariment (VCI)

血管认知障碍 (VCI) 的内皮机制

基本信息

批准号：
8583819
负责人：
Nabil J Alkayed
金额：
$ 23.1万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8583819
关键词：
Acids Affect Age Age-Months Alzheimer&apos s Disease Autopsy Biochemical Biological Availability Biological Markers Blood Vessels Brain Cells Cerebrum Chronic Code Cognitive Common carotid artery Data Dementia Deposition Development Diagnosis Diffuse Disease Elderly Endothelial Cells Endothelium Endothelium-Dependent Relaxing Factors Enzymes Epoxide hydrolase Exhibits Extracellular Matrix Frequencies Functional disorder Gene Deletion Genes Genetic Gray unit of radiation dose Heart Histologic Human Hydrolase Gene Hypoxia Impaired cognition Impairment Incidence Infarction Injury Lead Lesion Leukoaraiosis Lipids Magnetic Resonance Imaging Mediating Microcirculation Mus Muscle Cells Neurocognitive Neurodegenerative Disorders Neuroglia Neurons Nitric Oxide Pathology Patients Perfusion Play Prevalence Procedures Property Research Role Signal Transduction Signaling Molecule Single Nucleotide Polymorphism Testing Tissues Transgenic Organisms Up-Regulation Vascular Cognitive Impairment Vascular Dementia Vascular Diseases Vascular Endothelium Vasodilator Agents Weight Wild Type Mouse age related arteriole artery occlusion base behavior test brain tissue cerebral hypoperfusion cerebrovascular gray matter human tissue inhibitor/antagonist mRNA Expression middle age mouse model neurobehavioral test prevent protein expression public health relevance research study response sham surgery vascular bed white matter white matter damage young adult

项目摘要

DESCRIPTION (provided by applicant): Vascular cognitive impairment (VCI) is the second most common cause of dementia after Alzheimer's disease (AD). Unfortunately, VCI remains poorly understood, with no specific treatment, in part due to lack of understanding of underlying mechanisms of the disease. The most common cause of VCI is cerebral small vessel disease (SVD), an age-related vasculopathy primarily affecting deep penetrating end-arterioles supplying subcortical gray and periventricular and deep white matter. SVD is seen radiologically as isolated lacunar infarcts or diffuse ischemic white matter lesions (WML, called leukoaraiosis). WML are common in the elderly brain and are particularly prevalent in aging-related neurodegenerative disorders, including AD and VCI. The most consistent pathological finding in WML is cerebral microangiopathy, pathological changes in small intraparenchymal cerebral arterioles, which may lead to foci of chronic hypoperfusion and subsequent ischemic changes in white matter. The mechanisms underlying VCI and SVD in particular are poorly understood, and no specific treatments currently exist to prevent or treat SVD and associated VCI. There is evidence, however, that SVD involves endothelial injury and dysfunction. Accumulating evidence suggests that dilation of large vessels is primarily regulated by the endothelium-derived nitric oxide (NO), whereas in small vessels, it is additionally regulated by the endothelium-dependent hyperpolarizing factor (EDHF), which plays a particularly important role in small vessels after injury. Evidence from several vascular beds, including heart suggests that a group of endothelial-derived lipid signaling molecules called EETs (epoxyeicosatrienoic acids) may mediate EDHF response in the microcirculation. In addition to being vasodilators, EETs have neuroprotective properties, and protect neurons and glia from ischemic injury. Our preliminary data in postmortem human tissue from patients with SVD demonstrate that the enzyme that metabolizes and inactivates EETs, called soluble epoxide hydrolase (sEH), is upregulated in small cerebral vessels in SVD. Upregulation of sEH reduces the bioavailability of EETs in the microenvironment surrounding these vessels, rendering downstream and neighboring cells susceptible to hypoxic ischemic injury. In the current proposal, we will use a mouse model of chronic cerebral hypoperfusion to determine if sEH is causally and mechanistically involved in cerebrovascular pathology and neurocognitive decline in VCI. We will test the hypothesis that chronic hypoperfusion induces microvascular sEH expression, which further reduces tissue perfusion and leads to WML and cognitive impairment, and that mice with endothelial-specific expression of human sEH will exhibit accelerated age-dependent vascular pathology, WML and neurocognitive decline, while mice with sEH inhibition and gene deletion will be protected.

描述（由申请人提供）：血管认知障碍（VCI）是仅次于阿尔茨海默氏病（AD）的第二常见痴呆症原因。不幸的是，VCI仍然对没有特定治疗的理解不足，部分原因是缺乏对疾病的潜在机制的了解。 VCI的最常见原因是脑小血管疾病（SVD），这是一种与年龄相关的血管病，主要影响深层穿透性的末端 - 供应亚皮层灰色，脑膜周围和深层白质。 SVD在放射学上被视为孤立的lacunar梗塞或弥漫性缺血性白质病变（WML，称为白质病）。 WML在老年大脑中很常见，在与衰老有关的神经退行性疾病（包括AD和VCI）中尤为普遍。 WML中最一致的病理发现是脑微血管病，小脑内大脑小动脉中的病理变化，这可能导致慢性灌注不足的焦点以及随后的白质缺血性变化。尤其是对VCI和SVD的机制尤其了解，目前尚无特定的治疗方法来预防或治疗SVD和相关的VCI。但是，有证据表明，SVD涉及内皮损伤和功能障碍。积累的证据表明，大血管的扩张主要受内皮衍生的一氧化氮（NO）调节，而在小血管中，它又受受伤后的小容器在小容器中起着特别重要的作用。包括心脏在内的几个血管床的证据表明，一组称为EET的内皮衍生的脂质信号分子（环氧酸性酸）可能会介导微循环中的EDHF反应。除了血管扩张剂外，EET还具有神经保护特性，并保护神经元和神经胶质免受缺血性损伤。 SVD患者的死后人体组织中我们的初步数据表明，在SVD中的小脑血管中上调了代谢和失活的EET的酶，称为可溶性环氧水解酶（SEH）。 SEH的上调降低了围绕这些血管的微环境中EET的生物利用度，使下游和邻近的细胞容易受到低氧缺血性损伤的影响。在当前的提案中，我们将使用慢性脑灌注灌注的小鼠模型来确定SEH是否在VCI中与脑血管病理学和神经认知下降有关。我们将检验以下假设：慢性灌注诱导的微血管SEH表达，这进一步降低了组织灌注并导致WML和认知障碍，而人类SEH的内皮特异性表达的小鼠将表现出加速依赖年龄的血管病理病理学，WML和神经认知的依赖，同时与SEH相同，并且Seh seh seh and seh and seh seh。