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，没有特定的治疗方法，部分原因是缺乏对该疾病潜在机制的了解。VCI最常见的病因是脑血管病（SVD），这是一种与年龄相关的血管病变，主要影响供应皮层下灰质、心室周围和深部白质的深穿透性终小动脉。SVD在影像学上表现为孤立的腔隙性梗死或弥漫性缺血性白质病变（WML，称为白质病变）。WML常见于老年人大脑，尤其常见于与年龄相关的神经退行性疾病，包括AD和VCI。WML最一致的病理表现是脑微血管病变，脑实质内小动脉的病理改变，可能导致慢性灌注不足的病灶和随后的白质缺血性改变。VCI和SVD的发病机制尚不清楚，目前还没有专门的治疗方法来预防或治疗SVD和相关的VCI。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，而小血管的扩张则由内皮依赖性超极化因子（EDHF）调节，EDHF在小血管损伤后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，一组内皮来源的脂质信号分子EETs（环氧二碳三烯酸）可能在微循环中介导EDHF反应。除了作为血管扩张剂外，eet还具有神经保护特性，可以保护神经元和胶质细胞免受缺血性损伤。我们在SVD患者的死后人体组织中的初步数据表明，SVD患者的小脑血管中代谢和灭活eet的酶，即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eet的生物利用度，使下游和邻近细胞容易受到缺氧缺血性损伤。在目前的建议中，我们将使用慢性脑灌流不足的小鼠模型来确定sEH是否与VCI的脑血管病理和神经认知能力下降有因果和机制上的关系。我们将验证以下假设：慢性低灌注诱导微血管sEH表达，进一步减少组织灌注，导致WML和认知功能障碍；内皮特异性表达人类sEH的小鼠会加速年龄依赖性血管病理、WML和神经认知功能下降，而sEH抑制和基因缺失的小鼠则会受到保护。

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.