Hypoxia interferes with aryl hydrocarbon receptor pathway in hCMEC/D3 human cerebral microvascular endothelial cells. (14th November 2014)

• Record Type: Journal Article
• Authors: Jacob, Aude; Potin, Sophie; Saubaméa, Bruno; Crete, Dominique; Scherrmann, Jean‐Michel; Curis, Emmanuel; Peyssonnaux, Carole; Declèves, Xavier
• Is Part Of: Journal of neurochemistry. Volume 132:Number 4(2015:Feb.)
• Page Start: 373
• Page End: 383
• Publication Date: 2014-11-14
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.12972
• Languages: English
• ISSNs: 0022-3042

Abstract

<abstract abstract-type="main" id="jnc12972-abs-0001"> <title>Abstract</title> <p>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 <italic>VEGF</italic> and <italic>GLUT‐1</italic>. 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 <italic>CYP1A1</italic> and <italic>CYP1B1</italic> 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. <boxed-text content-type="graphic" id="jnc12972-blkfxd-1001" position="anchor" orientation="portrait"><graphic position="anchor" mimetype="image" xlink:href="ark:/27927/pgjdq2nt36" orientation="portrait" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /></boxed-text></p> <p>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 <italic>CYP1A1</italic> and <italic>CYP1B1</italic>, AhR activation results in no change in hypoxia target gene expression. This is the first sign of AhR and hypoxia pathway crosstalk in an <italic>in vitro</italic> model of the human cerebral endothelium.</p> </abstract>