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Hypoxia selectively disrupts brain microvascular endothelial tight junction complexes through a hypoxia-inducible factor-1 (HIF-1) dependent mechanism


Engelhardt, Sabrina; Al-Ahmad, Abraham J; Gassmann, Max; Ogunshola, Omolara O (2014). Hypoxia selectively disrupts brain microvascular endothelial tight junction complexes through a hypoxia-inducible factor-1 (HIF-1) dependent mechanism. Journal of Cellular Physiology, 229(8):1096-1105.

Abstract

The blood-brain barrier (BBB) constitutes a critical barrier for the maintenance of central nervous system homeostasis. Brain microvascular endothelial cells line the vessel walls and express tight junction (TJ) complexes that restrict paracellular passage across the BBB, thereby fulfilling a crucial role in ensuring brain function. Hypoxia, an impaired O2 delivery, is known to cause BBB dysfunction but the mechanisms that drive this disruption remain unclear. This study discloses the relevance of the master regulator of the hypoxic response, hypoxia-inducible factor-1 (HIF-1), in hypoxia-induced barrier disruption using the rat brain endothelial cell line RBE4. Hypoxic exposure rapidly induced stabilization of the HIF-1 oxygen-dependent alpha subunit (HIF-1α) concomitantly with BBB impairment and TJ disruption mainly through delocalization and increased tyrosine phosphorylation of TJ proteins. Similar observations were obtained by normoxic stabilization of HIF-1α using CoCl2 , deferoxamine, and dimethyloxalylglycine underlining the involvement of HIF-1 in barrier dysfunction particularly via TJ alterations. In agreement inhibition of HIF-1 stabilization by 2-methoxyestradiol and YC-1 improved barrier function in hypoxic cells. Overall our data suggests that activation of HIF-1-mediated signaling disrupts TJ resulting in increased BBB permeability. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.

Abstract

The blood-brain barrier (BBB) constitutes a critical barrier for the maintenance of central nervous system homeostasis. Brain microvascular endothelial cells line the vessel walls and express tight junction (TJ) complexes that restrict paracellular passage across the BBB, thereby fulfilling a crucial role in ensuring brain function. Hypoxia, an impaired O2 delivery, is known to cause BBB dysfunction but the mechanisms that drive this disruption remain unclear. This study discloses the relevance of the master regulator of the hypoxic response, hypoxia-inducible factor-1 (HIF-1), in hypoxia-induced barrier disruption using the rat brain endothelial cell line RBE4. Hypoxic exposure rapidly induced stabilization of the HIF-1 oxygen-dependent alpha subunit (HIF-1α) concomitantly with BBB impairment and TJ disruption mainly through delocalization and increased tyrosine phosphorylation of TJ proteins. Similar observations were obtained by normoxic stabilization of HIF-1α using CoCl2 , deferoxamine, and dimethyloxalylglycine underlining the involvement of HIF-1 in barrier dysfunction particularly via TJ alterations. In agreement inhibition of HIF-1 stabilization by 2-methoxyestradiol and YC-1 improved barrier function in hypoxic cells. Overall our data suggests that activation of HIF-1-mediated signaling disrupts TJ resulting in increased BBB permeability. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
05 Vetsuisse Faculty > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2014
Deposited On:11 Feb 2014 12:46
Last Modified:05 Apr 2016 17:32
Publisher:Wiley-Blackwell
ISSN:0021-9541
Publisher DOI:https://doi.org/10.1002/jcp.24544
PubMed ID:24375098

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