在内皮细胞表达人EPHX2的转基因小鼠中出现的年龄依赖性认知障碍、脑积水和白细胞浸润。
Age-dependent cognitive impairment, hydrocephalus and leukocyte infiltration in transgenic mice with endothelial expression of human EPHX2.
作者信息
Davis Catherine M, Zhang Wenri H, Bah Thierno M, Roese Natalie E, Allen Elyse M, Leung Philberta, Boutros Sydney J, Marzulla Tessa, Patel Esha, Nie Xiao, Alkayed Farah N, Huang Justin H, Jensen Michael A, Raber Jacob, Pike Martin M, Alkayed Nabil J
机构信息
Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR, 97239, USA.
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA.
出版信息
NPJ Aging. 2022 Jul 5;8(1):9. doi: 10.1038/s41514-022-00090-1.
Soluble epoxide hydrolase (sEH) is upregulated in microvascular endothelium of human brain with vascular cognitive impairment (VCI). Transgenic endothelial expression of human sEH in mice (Tie2hsEH) induces endothelial dysfunction (ED), a pathogenetic mechanism of VCI. We sought to determine if endothelial upregulation of sEH is sufficient to cause cognitive impairment, and if cognitive impairment due to chronic hypoperfusion induced by unilateral common carotid artery occlusion (CCAO) is exacerbated in Tie2hsEH mice. Behavioral performance was assessed by the open field, rotarod, novel object, Morris water maze and fear conditioning tests. Cerebral blood flow and brain morphology were evaluated by MRI, and inflammatory changes investigated using immunohistochemistry and flow cytometry. We demonstrate that transgenic endothelial expression of sEH is sufficient to induce cognitive impairment, associated with leukocyte infiltration, brain atrophy and accelerated, age-dependent ventriculomegaly, identifying ED and sEH upregulation as potential underlying mechanisms and therapeutic targets for VCI.
可溶性环氧化物水解酶（sEH）在患有血管性认知障碍（VCI）的人类大脑微血管内皮细胞中上调。在小鼠中进行人sEH的转基因内皮表达（Tie2hsEH）会诱导内皮功能障碍（ED），这是VCI的一种发病机制。我们试图确定内皮细胞中sEH的上调是否足以导致认知障碍，以及在Tie2hsEH小鼠中，单侧颈总动脉闭塞（CCAO）引起的慢性灌注不足所致的认知障碍是否会加剧。通过旷场试验、转棒试验、新物体试验、莫里斯水迷宫试验和恐惧条件反射试验评估行为表现。通过磁共振成像（MRI）评估脑血流量和脑形态，并使用免疫组织化学和流式细胞术研究炎症变化。我们证明，sEH的转基因内皮表达足以诱导认知障碍，这与白细胞浸润、脑萎缩以及加速的、年龄依赖性脑室扩大有关，从而确定ED和sEH上调是VCI潜在的潜在机制和治疗靶点。
Zotero 插件