Endothelial Mechanism of Vascular Cognitive Impariment (VCI)

描述（由申请人提供）：血管性认知障碍（VCI）是仅次于阿尔茨海默病（AD）的痴呆症的第二大常见原因。不幸的是，VCI仍然知之甚少，没有具体的治疗方法，部分原因是缺乏对疾病潜在机制的了解。VCI最常见的原因是脑小血管病（SVD），这是一种年龄相关的血管病变，主要影响供应皮质下灰质、脑室周围和深部白色物质的深穿透性终末小动脉。SVD在放射学上表现为孤立的腔隙性梗死或弥漫性缺血性白色病变（WML，称为脑白质疏松）。WML在老年人大脑中很常见，在与衰老相关的神经退行性疾病（包括AD和VCI）中尤其普遍。WML中最一致的病理学发现是脑微血管病，即脑实质内小动脉的病理学变化，可能导致慢性低灌注灶和随后的白色物质缺血性变化。特别是VCI和SVD的潜在机制知之甚少，目前还没有预防或治疗SVD和相关VCI的特异性治疗方法。然而，有证据表明，SVD涉及内皮损伤和功能障碍。越来越多的证据表明，大血管的扩张主要由内皮源性一氧化氮（NO）调节，而在小血管中，它还由内皮依赖性超极化因子（EDHF）调节，EDHF在损伤后的小血管中起着特别重要的作用。来自包括心脏在内的几个血管床的证据表明，一组内皮源性的脂质信号分子EHF（环氧二十碳三烯酸）可能介导微循环中的EDHF反应。除了作为血管扩张剂之外，雌二醇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。我们对SVD患者死后人体组织的初步数据表明，在SVD的小脑血管中，代谢和灭活Ehrs的酶（称为可溶性环氧化物水解酶（sEH））上调。sEH的上调降低了这些血管周围微环境中的雌二醇的生物利用度，使下游和邻近细胞对缺氧缺血性损伤敏感。在目前的建议中，我们将使用慢性脑灌注不足的小鼠模型，以确定是否sEH是因果关系和机械参与脑血管病变和VCI的神经认知能力下降。我们将检验以下假设：慢性低灌注诱导微血管sEH表达，其进一步减少组织灌注并导致WML和认知障碍，并且具有内皮特异性表达人sEH的小鼠将表现出加速的年龄依赖性血管病理学、WML和神经认知下降，而具有sEH抑制和基因缺失的小鼠将受到保护。

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.