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.

患有血管性认知障碍（VCI）的人脑微血管内皮中可溶性环氧化物水解酶（sEH）上调。小鼠体内人 sEH 的转基因内皮表达 (Tie2hsEH) 会诱导内皮功能障碍 (ED)，这是 VCI 的发病机制。我们试图确定 sEH 的内皮上调是否足以引起认知障碍，以及 Tie2hsEH 小鼠中单侧颈总动脉闭塞 (CCAO) 引起的慢性灌注不足导致的认知障碍是否会加剧。通过开放场地、旋转棒、新物体、莫里斯水迷宫和恐惧条件反射测试来评估行为表现。通过 MRI 评估脑血流和脑形态，并使用免疫组织化学和流式细胞术研究炎症变化。