TY - JOUR
T1 - Kruppel-like factor 2 protects against ischemic stroke by regulating endothelial blood brain barrier function
AU - Shi, Hong
AU - Sheng, Baiyang
AU - Zhang, Feng
AU - Wu, Chunying
AU - Zhang, Rongli
AU - Zhu, Junqing
AU - Xu, Kui
AU - Kuang, Youzhi
AU - Jameson, Stephen C.
AU - Lin, Zhiyong
AU - Wang, Yanming
AU - Chen, Jun
AU - Jain, Mukesh K.
AU - Atkins, G. Brandon
PY - 2013
Y1 - 2013
N2 - 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 (KLF2tg), 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, KLF2tg 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.
AB - 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 (KLF2tg), 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, KLF2tg 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.
KW - Blood brain barrier
KW - Cerebrovascular disease
KW - Endothelial cells
KW - Kruppel-like factor 2
KW - Stroke
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U2 - 10.1152/ajpheart.00712.2012
DO - 10.1152/ajpheart.00712.2012
M3 - Article
C2 - 23335794
AN - SCOPUS:84878613638
SN - 0363-6135
VL - 304
SP - H796-H805
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 6
ER -