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Introduction: Krüppel-like factors (KLFs) belong to zinc finger family of transcription factors and their roles in stroke are poorly explored. KLF11 is highly enriched in vascular endothelium, and we have previously documented that peroxisome proliferator-activated receptor gamma-mediated cerebral protection during ischemic insults needs KLF11 as a critical coactivator. However, the role of endothelial KLF11 itself in cerebrovascular function and stroke outcome is unclear.Hypothesis: We hypothesize that endothelium-targeted overexpression of KLF11 stabilizes the BBB, reduces the progression of brain damage, and improves neurological outcomes after ischemic stroke.Methods: Transient middle cerebral artery occlusion was performed in endothelial cell-selective KLF11 transgenic mice (EC-KLF11 Tg), and WT controls. BBB integrity was assessed by using Evans Blue and TMR-Dextran extravasation assays. Brain water content was measured by using a dry-wet method. Brain infarct was analyzed by 2%TTC staining. A battery of neurobehavioral tests, including rotarod, adhesive tape removal, and foot fault, were performed to assess sensorimotor functions. Total RNA was extracted from brain tissues and the expression of BBB tight junctions (TJs) was detected by qPCR and western blotting.Results: Compared to WT controls, EC-selective transgenic overexpression of KLF11 led to reduced BBB leakage in ischemic brains, evidenced by significantly reduced extravasation of BBB tracers and less brain water content. EC-KLF11 Tg mice also exhibited a smaller brain infarct and improved neurological functions in response to ischemic insults. Mechanistically, we found KLF11 binding sites in the promoter region of major endothelial TJs including Claudin 5 and ZO-1. EC-selective transgenic overexpression of KLF11 significantly increased cerebral TJ levels in mice after ischemic stroke.Conclusions: The present study has demonstrated that KLF11 functions at the EC level to preserve BBB structural and functional integrity and confers brain protection in ischemic stroke. KLF11 may be a novel therapeutic target for the treatment of ischemic stroke.