Hypoxia Selectively Disrupts Brain Microvascular Endothelial Tight Junction Complexes Through a Hypoxia‐Inducible Factor‐1 (HIF‐1) Dependent Mechanism

Engelhardt, Sabrina; Al‐Ahmad, Abraham; Gassmann, Max; Ogunshola, Omolara O.

doi:10.1002/jcp.24544

Cited by 111 publications

(118 citation statements)

References 52 publications

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“…However, most of these studies were focused on epithelial TJs, and therefore, the role of phosphorylation of TJ proteins in the preservation or perturbation of endothelial TJ integrity and its barrier function has not been well-studied. In this context, a few studies, including ours, showed that phosphorylation of TJ proteins leads to endothelial TJ disruption and loss of its barrier function ( 20,21,42,43 ). In the present study, we have extended our previous observations on the role of tyrosine phosphorylation of TJ proteins in the disruption of TJ integrity and barrier function to JamA.…”

Section: Xo-dependent Ros Production Mediates 15(s)-heteinduced Jama supporting

confidence: 81%

12/15-Lipoxygenase-dependent ROS production is required for diet-induced endothelial barrier dysfunction

Chattopadhyay

Tinnikov

Dyukova

et al. 2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org surface to the circulating blood, and releases vasoactive substances involved in the regulation of vascular tone ( 1, 2 ). Besides, it selectively permits the movement of molecules into and out of the bloodstream, and this semipermeable capacity of the endothelial monolayer depends majorly on cell-to-cell connections, namely adherens junctions (AJs), tight junctions (TJs), and gap junctions ( 3, 4 ). Disruption of these junctions leads to a leaky endothelial barrier, which allows the traffi cking of leukocytes through the blood vessels into the interstitial space and initiates infl ammation ( 2, 4 ). A large body of evidence indicates that TJs of endothelium play a pivotal role in modulating its barrier permeability, and dysfunctional endothelium often manifests increased barrier permeability ( 5, 6 ). Many studies suggest that oxidative stress is one of the underlying factors in endothelial dysfunction and atherosclerosis ( 7,8 ). NADPH oxidase, a major source of reactive oxygen species (ROS) production ( 9 ), has been reported to increase EC barrier permeability ( 10, 11 ). Xanthine oxidase (XO), a purine-catabolizing enzyme, was also found as another major source of cellular ROS production ( 12 ). XO results from sulfhydryl oxidation or proteolytic conversion of xanthine dehydrogenase (XDH) ( 13,14 ). Although both XDH and XO convert hypoxanthine and xanthine to uric acid, XO preferentially converts molecular oxygen to superoxide anion and hydrogen peroxide ( 12 ). However, under the reduced state, XDH can also react with molecular oxygen and generate ROS ( 15 ). Although the physiological signifi cance of XDH conversion to XO is not clear, XO was found to be abundantly present in several tissues, including in the luminal surface of the microvascular endothelium, and is thought to be involved in the pathogenesis of various diseases such as infl ammation and Endothelium, which is constituted by a monolayer of endothelial cells (ECs), is the inner most lining of the blood vessels, provides nonplatelet adherent nonthrombotic Abstract To understand the mechanisms of 15(S)-HETEinduced endothelial cell (EC) barrier dysfunction, we examined the role of xanthine oxidase (XO). 15(S)-HETE induced

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Section: Xo-dependent Ros Production Mediates 15(s)-heteinduced Jama supporting

confidence: 81%

12/15-Lipoxygenase-dependent ROS production is required for diet-induced endothelial barrier dysfunction

Chattopadhyay

Tinnikov

Dyukova

et al. 2015

Journal of Lipid Research

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“…Hypoxia [21,25,[168][169][170] and ischemia [171] have been shown to induce BBB permeability by altering the expression of junctional proteins. Importantly, the combined effect of hypoxia and aglycemia appears to enhance the increased BBB permeability produced by hypoxia alone [172].…”

Section: Endothelial Response To Chronic Hypoperfusion-related Hypoximentioning

confidence: 99%

“…Hypoxia induces BBB permeability [21,25,[168][169][170], ROS generation [160,161] and stimulates proinflammatory gene expression [18,162]. Hypoxia and inflammation may cooperate in inducing BBB permeability [21].…”

Section: Hypoxia/ischemiamentioning

confidence: 99%

“…BBB permeability is influenced by hypoxia/ischemia [21,25,[168][169][170]172], inflammation [19], oxidative stress [15], and A [125][126][127][128]. Astrocytes also contribute to BBB permeability during inflammation by releasing inflammatory cytokines [34,35], and amplify the endothelial response to ischemia by increasing junctional permeability [225].…”

Section: Bbb Permeabilitymentioning

confidence: 99%

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Vascular dysfunction in the pathogenesis of Alzheimer's disease — A review of endothelium-mediated mechanisms and ensuing vicious circles

Marco

Venneri

Farkas

et al. 2015

Neurobiology of Disease

232

185

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Article available under the terms of the CC-BY-NC-ND licence (https://creativecommons.org/licenses/by-nc-nd/4.0/) eprints@whiterose.ac.uk https://eprints.whiterose.ac.uk/ Reuse Unless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version -refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher's website. TakedownIf you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request.

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“…Stroke results in the breakdown of the BBB, with subsequent damage to cerebral vasculature and nonvascular brain elements, including neurons, astrocytes, and microglia. Hypoxia‐induced vascular damage is associated with disruption of paracellular cell junctions, with selective targeting of brain microvascular endothelial TJ complexes 6, 7, 8…”

Section: Introductionmentioning

confidence: 99%

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Peña-Philippides

Gardiner

Caballero-Garrido

et al. 2018

JAHA

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BackgroundBrain microvascular endothelial cells form a highly selective blood brain barrier regulated by the endothelial tight junctions. Cerebral ischemia selectively targets tight junction protein complexes, which leads to significant damage to cerebral microvasculature. Short noncoding molecules called microRNAs are implicated in the regulation of various pathological states, including endothelial barrier dysfunction. In the present study, we investigated the influence of microRNA‐155 (miR‐155) on the barrier characteristics of human primary brain microvascular endothelial cells (HBMECs).Methods and ResultsOxygen‐glucose deprivation was used as an in vitro model of ischemic stroke. HBMECs were subjected to 3 hours of oxygen‐glucose deprivation, followed by transfections with miR‐155 inhibitor, mimic, or appropriate control oligonucleotides. Intact normoxia control HBMECs and 4 oxygen‐glucose deprivation–treated groups of cells transfected with appropriate nucleotide were subjected to endothelial monolayer electrical resistance and permeability assays, cell viability assay, assessment of NO and human cytokine/chemokine release, immunofluorescence microscopy, Western blot, and polymerase chain reaction analyses. Assessment of endothelial resistance and permeability demonstrated that miR‐155 inhibition improved HBMECs monolayer integrity. In addition, miR‐155 inhibition significantly increased the levels of major tight junction proteins claudin‐1 and zonula occludens protein‐1, while its overexpression reduced these levels. Immunoprecipitation and colocalization analyses detected that miR‐155 inhibition supported the association between zonula occludens protein‐1 and claudin‐1 and their stabilization at the HBMEC membrane. Luciferase reporter assay verified that claudin‐1 is directly targeted by miR‐155.ConclusionsBased on these results, we conclude that miR‐155 inhibition–induced strengthening of endothelial tight junctions after oxygen‐glucose deprivation is mediated via its direct target protein claudin‐1.

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Hypoxia Selectively Disrupts Brain Microvascular Endothelial Tight Junction Complexes Through a Hypoxia‐Inducible Factor‐1 (HIF‐1) Dependent Mechanism

Cited by 111 publications

References 52 publications

12/15-Lipoxygenase-dependent ROS production is required for diet-induced endothelial barrier dysfunction

12/15-Lipoxygenase-dependent ROS production is required for diet-induced endothelial barrier dysfunction

Vascular dysfunction in the pathogenesis of Alzheimer's disease — A review of endothelium-mediated mechanisms and ensuing vicious circles

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

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