title: Kruppel-like factor 2 protects against ischemic stroke by regulating endothelial blood brain barrier function.
abstract: During an ischemic stroke normal brain endothelial function is perturbed, resulting in blood brain barrier (BBB) breakdown with subsequent infiltration of activated inflammatory blood cells, ultimately leading to neuronal cell death. Kruppel-like factor 2 (KLF2) is regulated by flow, is highly expressed in vascular endothelial cells (ECs), and serves as a key molecular switch regulating endothelial function and promoting vascular health. In this study we sought to determine the role of KLF2 in cerebrovascular function and the pathogenesis of ischemic stroke. Transient middle cerebral artery occlusion was performed in KLF2-deficient (KLF2(-/-)), KLF2 overexpressing (KLF2(tg)), and control mice, and stroke volume was analyzed. BBB function was assessed in vivo by real-time neuroimaging using positron emission tomography and Evan's blue dye assay. KLF2(-/-) mice exhibited significantly larger strokes and impairment in BBB function. In contrast, KLF2(tg) mice were protected against ischemic stroke and demonstrated preserved BBB function. In concordance, gain- and loss-of-function studies in primary brain microvascular ECs using transwell assays revealed KLF2 to be BBB protective. Mechanistically, KLF2 was demonstrated, both in vitro and in vivo, to regulate the critical BBB tight junction factor occludin. These data are first to identify endothelial KLF2 as a key regulator of the BBB and a novel neuroprotective factor in ischemic stroke.
authors: Harrington Heart and Vascular Institute, Case Cardiovascular Research Institute, Department of Medicine, University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors: Hong
authors: H
authors: Shi
authors: Baiyang
authors: B
authors: Sheng
authors: Feng
authors: F
authors: Zhang
authors: Chunying
authors: C
authors: Wu
authors: Rongli
authors: R
authors: Zhang
authors: Junqing
authors: J
authors: Zhu
authors: Kui
authors: K
authors: Xu
authors: Youzhi
authors: Y
authors: Kuang
authors: Stephen C
authors: SC
authors: Jameson
authors: Zhiyong
authors: Z
authors: Lin
authors: Yanming
authors: Y
authors: Wang
authors: Jun
authors: J
authors: Chen
authors: Mukesh K
authors: MK
authors: Jain
authors: G Brandon
authors: GB
authors: Atkins
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000000981:diagnostic imaging / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D064847:Multimodal Imaging; D062793:Occludin / Q000235:genetics / Q000378:metabolism; D049268:Positron-Emission Tomography; D014057:Tomography, X-Ray Computed
chemical_list: C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D062793:Occludin