Reactive oxygen species alter brain endothelial tight junction dynamics via RhoA, PI3 kinase and PKB signaling
Abstract
ABSTRACT The blood‐brain barrier (BBB) prevents the entrance of circulating molecules and immune cells into the central nervous system. The barrier is formed by specialized brain endothelial cells that are interconnected by tight junctions (TJ). A defective function of the BBB has been described for a variety of neuroinflammatory diseases, indicating that proper regulation is essential for maintaining brain homeostasis. Under pathological conditions, reactive oxygen species (ROS) significantly contribute to BBB dysfunction and inflammation in the brain by enhancing cellular migration. However, a detailed study about the molecular mechanism by which ROS alter BBB integrity has been lacking. Here we demonstrate that ROS alter BBB integrity, which is paralleled by cytoskel‐eton rearrangements and redistribution and disappearance of TJ proteins claudin‐5 and occludin. Specific signaling pathways, including RhoA and PI3 kinase, mediated observed processes and specific inhibitors of these pathways prevented ROS‐induced monocyte migration across an in vitro model of the BBB. Interestingly, these processes were also mediated by protein kinase B (PKB/ Akt), a previously unknown player in cytoskeleton and TJ dynamics that acted downstream of RhoA and PI3 kinase. Our study reveals new insights into molecular mechanisms underlying BBB regulation and provides novel opportunities for the treatment of neuroinflammatory diseases.—Schreibelt, G., Kooij, G., Reijerkerk, A., van Doorn, R., Gringhuis, S. I., van der Pol, S., Weksler, B. B., Romero, I. A., Couraud, P.‐O., Piontek, J., Blasig, I. E., Dijkstra, C. D., Ronken, E., de Vries, H. E. Reactive oxygen species alter brain endothelial tight junction dynamics via RhoA, PI3 kinase and PKB signaling. FASEB J. 21, 3666–3676 (2007)
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Binding of Aβ with endothelial RAGE receptor induces oxidative stress via NOX and ROS, ultimately inducing inflammation and impairing tight junctions, leading to loss of BBB integrity and interruption of cerebral blood flow.
“Binding of Aβ with endothelial RAGE receptor also induced oxidative stress, as indicated by improved NADPH oxidase (NOX) and increased the generation of ROS (primarily peroxynitrite), which ultimately induced inflammation and impaired tight junctions, leading to loss of BBB integrity481,482 and interruption of cerebral blood flow.483”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [482]
ROS and NO can reorganize the cytoskeleton of endothelial cells and modulate tight junction proteins claudin-5 and occludin.
“In addition, ROS and NO can also reorganize the cytoskeleton of ECs and modulate tight junction proteins claudin-5 and occludin (Yamagata et al., 2004; Schreibelt et al., 2007) activate microglial cells; and up-regulate inflammatory mediators in the first 48 h.”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Schreibelt et al., 2007
ROS and NO activate microglial cells and up-regulate inflammatory mediators in the first 48 h.
“In addition, ROS and NO can also reorganize the cytoskeleton of ECs and modulate tight junction proteins claudin-5 and occludin (Yamagata et al., 2004; Schreibelt et al., 2007) activate microglial cells; and up-regulate inflammatory mediators in the first 48 h.”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Schreibelt et al., 2007
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- Authors
- Schreibelt, G., Kooij, G., Reijerkerk, A., van Doorn, R., Gringhuis, S. I., van der Pol, S., Weksler, B. B., Romero, I. A., Couraud, P., Piontek, J., Blasig, I. E., Dijkstra, C. D., Ronken, E., & de Vries, H. E.
- Affiliations
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Department of Molecular Cell Biology and Immunology VU University Medical Center Amsterdam The Netherlands
- Cornell University (US)
- The Open University (GB)
- Institut Cochin (FR)
- Institute of Molecular Pharmacology Berlin Germany
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
- Solvay (Netherlands) (NL)
- ORCID
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2007-06-22
- Volume
- 21
- Issue
- 13
- Pages
- 3666-3676
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2112523443
- Cited by
- 347
- References
- 64
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 24 · 2023: 13 · 2022: 26 · 2021: 18 · 2020: 19 · 2019: 13 · 2018: 19 · 2017: 11 · 2016: 17 · 2015: 23 · 2014: 24 · 2013: 15 · 2012: 20
- FWCI
- 11.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Open Research Online (The Open University) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- reactive oxygen species, blood-brain barrier, tight junctions, brain endothelial cells, RhoA signaling, PI3K signaling, Akt signaling, claudin-5, occludin, cytoskeleton rearrangement, monocyte migration, neuroinflammation, barrier dysfunction
- MeSH terms
- Animals, Cell Line, Transformed, Humans, Signal Transduction, Reactive Oxygen Species, Tight Junctions, Phosphatidylinositol 3-Kinases, rhoA GTP-Binding Protein, Proto-Oncogene Proteins c-akt, Rats
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