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Hypoxia interferes with aryl hydrocarbon receptor pathway in hCMEC /D3 human cerebral microvascular endothelial cells
Author(s) -
Jacob Aude,
Potin Sophie,
Saubaméa Bruno,
Crete Dominique,
Scherrmann JeanMichel,
Curis Emmanuel,
Peyssonnaux Carole,
Declèves Xavier
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12972
Subject(s) - aryl hydrocarbon receptor , hypoxia (environmental) , crosstalk , microbiology and biotechnology , signal transduction , transcription factor , aryl hydrocarbon receptor nuclear translocator , downregulation and upregulation , cyp1b1 , biology , cell culture , chemistry , cancer research , biochemistry , gene , cytochrome p450 , oxygen , metabolism , physics , organic chemistry , optics , genetics
Abstract The expression of aryl hydrocarbon receptor (AhR) transcription factor was detected at transcript level in freshly isolated human brain microvessels and in the hCMEC /D3 human cerebral microvascular endothelial cell line. Recent studies have demonstrated that AhR pathway is able to crosstalk with other pathways such as hypoxia signaling pathway. Therefore, we used the hCMEC /D3 cell line to investigate the potential crosstalk between AhR and hypoxia signaling pathways. First, we performed two different hypoxia‐like procedures in hCMEC /D3 cells; namely, exposition of cells to 150 μM deferoxamine or to glucose and oxygen deprivation for 6 h. These two procedures led to hypoxia‐inducible factor (HIF)‐1α and HIF‐2α proteins accumulation together with a significant induction of the two well‐known hypoxia‐inducible genes VEGF and GLUT‐1 . Both HIF‐1α and ‐2α functionally mediated hypoxia response in the hCMEC /D3 cells. Then, we observed that a 6 h exposure to 25 nM 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin, a strong AhR ligand, up‐regulated CYP1A1 and CYP1B1 expression, and that this effect was AhR dependent. Regarding AhR and hypoxia crosstalk, our experiments revealed that an asymmetric interference between these two pathways effectively occurred in hCMEC /D3 cells: hypoxia pathway interfered with AhR signaling but not the other way around.We studied the putative crosstalk of AhR and hypoxia pathways in hCMEC/D3 human cerebral microvascular endothelial cells. While hypoxia decreased the expression of the two AhR target genes CYP1A1 and CYP1B1 , AhR activation results in no change in hypoxia target gene expression. This is the first sign of AhR and hypoxia pathway crosstalk in an in vitro model of the human cerebral endothelium.