Microvascular endothelial cell (EC) injury and the subsequent blood‐brain barrier (BBB) breakdown are frequently seen in many neurological disorders, including stroke. We have previously documented that peroxisome proliferator‐activated receptor gamma (PPARγ)‐mediated cerebral protection during ischemic insults needs Krüppel‐like factor 11 (KLF11) as a critical coactivator. However, the role of endothelial KLF11 in cerebrovascular function and stroke outcome is unclear. This study is aimed at investigating the regulatory role of endothelial KLF11 in BBB preservation and neurovascular protection after ischemic stroke. EC‐targeted overexpression of KLF11 significantly mitigated BBB leakage in ischemic brains, evidenced by significantly reduced extravasation of BBB tracers and infiltration of peripheral immune cells, and less brain water content. Endothelial cell‐selective KLF11 transgenic (EC‐KLF11 Tg) mice also exhibited smaller brain infarct and improved neurological function in response to ischemic insults. Furthermore, EC‐targeted transgenic overexpression of KLF11 preserved cerebral tight junction (TJ) levels and attenuated the expression of pro‐inflammatory factors in mice after ischemic stroke. Mechanistically, we demonstrated that KLF11 directly binds to the promoter of major endothelial TJ proteins including occludin and ZO‐1 to promote their activities. Our data indicate that KLF11 functions at the EC level to preserve BBB structural and functional integrity, and therefore, confers brain protection in ischemic stroke. KLF11 may be a novel therapeutic target for the treatment of ischemic stroke and other neurological conditions involving BBB breakdown and neuroinflammation.

中文翻译：

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内皮素靶向的Krüppel样因子11的过表达保护缺血性脑损伤后的血脑屏障功能。

微血管内皮细胞（EC）损伤和随后的血脑屏障（BBB）破坏在许多神经系统疾病（包括中风）中屡见不鲜。我们先前已有文献证明，在缺血性损伤期间过氧化物酶体增殖物激活的受体γ（PPARγ）介导的脑保护需要Krüppel样因子11（KLF11）作为关键的共激活因子。然而，尚不清楚内皮KLF11在脑血管功能和中风预后中的作用。这项研究旨在调查缺血性卒中后内皮KLF11在BBB的保存和神经血管保护中的调节作用。EC靶向KLF11的过表达显着减轻了缺血性脑的BBB渗漏，其表现为BBB示踪剂的外渗显着减少和周围免疫细胞的浸润，以及脑水含量降低。内皮细胞选择性KLF11转基因（EC‐KLF11 Tg）小鼠对缺血性损伤也表现出较小的脑梗塞和改善的神经功能。此外，EC靶向的K​​LF11转基因过表达可保持缺血性中风后小鼠的大脑紧密连接（TJ）水平并减弱促炎因子的表达。从机制上讲，我们证明KLF11直接与主要的内皮TJ蛋白（包括occludin和ZO-1）的启动子结合以促进其活性。我们的数据表明，KLF11在EC级别发挥功能以保持BBB的结构和功能完整性，因此在缺血性卒中具有大脑保护作用。KLF11可能是治疗缺血性中风和其他涉及BBB分解和神经炎症的神经系统疾病的新型治疗靶标。