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beta-Catenin Is Required for Endothelial Cyp1b1 Regulation Influencing Metabolic Barrier Function
Goethe Univ Frankfurt, Edinger Inst, Inst Neurol, Sch Med, D-60528 Frankfurt, Germany..
Goethe Univ Frankfurt, Inst Vasc Signaling, D-60596 Frankfurt, Germany..
Goethe Univ Frankfurt, Inst Vasc Signaling, D-60596 Frankfurt, Germany.;German Ctr Cardiovasc Res, Partner Site Rhine Main, D-60528 Frankfurt, Germany..
Roche Diagnost GmbH, Roche Innovat Ctr Penzberg, Oncol, Pharma Res & Early Dev, D-82377 Penzberg, Germany..
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2016 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 36, no 34, 8921-8935 p.Article in journal (Refereed) Published
Abstract [en]

The canonical Wnt/beta-catenin signaling pathway is crucial for blood-brain barrier (BBB) formation in brain endothelial cells. Although glucose transporter 1, claudin-3, and plasmalemma vesicular-associated protein have been identified as Wnt/beta-catenin targets in brain endothelial cells, further downstream targets relevant to BBB formation and function are incompletely explored. By Affymetrix expression analysis, we show that the cytochrome P450 enzyme Cyp1b1 was significantly decreased in beta-catenin-deficient mouse endothelial cells, whereas its close homolog Cyp1a1 was upregulated in an aryl hydrocarbon receptor-dependent manner, hence indicating that beta-catenin is indispensable for Cyp1b1 but not for Cyp1a1 expression. Functionally, Cyp1b1 could generate retinoic acid from retinol leading to cell-autonomous induction of the barrier-related ATP-binding cassette transporter P-glycoprotein. Cyp1b1 could also generate 20-hydroxyeicosatetraenoic acid from arachidonic acid, decreasing endothelial barrier function in vitro. In mice in vivo pharmacological inhibition of Cyp1b1 increased BBB permeability for small molecular tracers, and Cyp1b1 was downregulated in glioma vessels in which BBB function is lost. Hence, we propose Cyp1b1 as a target of beta-catenin indirectly influencing BBB properties via its metabolic activity, and as a potential target for modulating barrier function in endothelial cells.

Place, publisher, year, edition, pages
2016. Vol. 36, no 34, 8921-8935 p.
Keyword [en]
beta-catenin, Cyp1b1, cytochrome P450, glioma, transcriptional regulation, Wnt signaling
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-305565DOI: 10.1523/JNEUROSCI.0148-16.2016ISI: 000384004000014PubMedID: 27559173OAI: oai:DiVA.org:uu-305565DiVA: diva2:1038621
Available from: 2016-10-19 Created: 2016-10-19 Last updated: 2016-10-19Bibliographically approved

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