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Vascular endothelial growth factor aggravates cerebral ischemia and reperfusion‐induced blood‐brain‐barrier disruption through regulating LOC102640519/HOXC13/ZO‐1 signaling

Li Wu,Zeming Ye,Ying Pan,Xianliang Li,Xi'an Fu,Bo Zhang,Youfu Li,Wanrong Lin,Xuelong Li,Qingchun Gao

Published 2018 in Experimental Cell Research

ABSTRACT

Background/objective Vascular endothelial growth factor (VEGF) has been recognized to be a potential pharmaceutical target for treating ischemic stroke, but its severe side effects hinder its widely application. Here, the present study was designed to investigate the effects of VEGF on blood‐brain‐barrier (BBB) disruption and the underlying mechanisms. Methods A mouse model of middle cerebral artery occlusion (MCAO) was constructed and treated with or without VEGF. Meanwhile, mice brain microvascular endothelial cells in co‐culture with astrocytes were subjected to 1, 2 and 4 h oxygen–glucose deprivation followed by 24 h of reperfusion (OGD/R) in the absence or presence of VEGF. The mRNA and protein expression were assessed by real‐time PCR and Western blotting. Fluorescence in situ hybridization (FISH) was utilized to validate LOC102640519 expression in OGD/R cell models. Chromatin Immunoprecipitation (ChIP) assay was used to confirm the regulatory mechanism of LOC102640519 to HOXC13. Interactions between HOXC13 and ZO‐1 were measured by a luciferase reporter assay and RNA pull down assay. Results Our results showed that administration of VEGF significantly aggravated BBB by upregulating LOC102640519 and HOXC13 expression in vitro and vitro model of cerebral ischemia. Furthermore, LOC102640519 positively regulated the expression of HOXC13, thus negatively regulated the expression of ZO‐1, Occludin and Claudin‐5 in OGD/R model in the absence or presence of VEGF. Conclusions VEGF aggravated BBB disruption after cerebral I/R‐induced injury probably by increasing LOC102640519 and HOXC13 through inhibition of ZO‐1, Occludin and Claudin‐5.

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