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Cited by 219Barrier Structure and Function StudiesCell Adhesion Molecules ResearchDrug Transport and Resistance Mechanisms

Endothelial β-Catenin Signaling Is Required for Maintaining Adult Blood–Brain Barrier Integrity and Central Nervous System Homeostasis

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Tran, Khiem A., Zhang, Xianming, Predescu, Dan, Huang, Xiaojia, Machado, Roberto F., Göthert, Joachim R., Malik, Asrar B., Valyi-Nagy, Tibor +1 more·2016·Circulation
DOI 10.1161/circulationaha.115.015982PMC PMC4814374
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Abstract

Background—: The blood–brain barrier (BBB) formed by brain endothelial cells interconnected by tight junctions is essential for the homeostasis of the central nervous system. Although studies have shown the importance of various signaling molecules in BBB formation during development, little is known about the molecular basis regulating the integrity of the adult BBB. Methods and Results—: Using a mouse model with tamoxifen-inducible endothelial cell–restricted disruption of ctnnb1 ( iCKO ), we show here that endothelial β-catenin signaling is essential for maintaining BBB integrity and central nervous system homeostasis in adult mice. The iCKO mice developed severe seizures accompanied by neuronal injury, multiple brain petechial hemorrhages, and central nervous system inflammation, and all had postictal death. Disruption of endothelial β-catenin induced BBB breakdown and downregulation of the specific tight junction proteins claudin-1 and -3 in adult brain endothelial cells. The clinical relevance of the data is indicated by the observation of decreased expression of claudin-1 and nuclear β-catenin in brain endothelial cells of hemorrhagic lesions of hemorrhagic stroke patients. Conclusions—: These results demonstrate the prerequisite role of endothelial β-catenin in maintaining the integrity of adult BBB. The results suggest that BBB dysfunction secondary to defective β-catenin transcription activity is a key pathogenic factor in hemorrhagic stroke, seizure activity, and central nervous system inflammation.

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Authors
Tran, K. A., Zhang, X., Predescu, D., Huang, X., Machado, R. F., Göthert, J. R., Malik, A. B., Valyi-Nagy, T., & Zhao, Y.-Y.
Affiliations
  • University of Illinois Chicago (US)
  • From Department of Pharmacology (K.A.T., X.Z., X.H., A.B.M., Y.Y.Z), Center for Lung and Vascular Biology (K.A.T., X.Z., X.H., A.B.M., Y.Y.Z), Department of Medicine (R.F.M.), and Department of Pathology (T.V.-N.), University of Illinois College of Medicine, Chicago; Department of Pharmacology, Rush University, Chicago, IL (D.P.); and Department of Hematology, West German Cancer Center, University Hospital Essen, Essen, Germany (J.R.G.).
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2016-01-12
Volume
133
Issue
2
Pages
177-186
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.115.015982
PMC
PMC4814374
OpenAlex
W2237670736
Cited by
219
References
5
Citations by year
2026: 14 · 2025: 28 · 2024: 17 · 2023: 32 · 2022: 27 · 2021: 27 · 2020: 18 · 2019: 22 · 2018: 14 · 2017: 16 · 2016: 4
FWCI
6.04
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
Funders
National Heart, Lung, and Blood Institute (R01HL085462, R56HL085462, P01HL060678, R01HL125350, P01HL077806, R01HL123957, T32HL007829, R01HL111656)
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
blood-brain barrier integrity, brain endothelial cells, tight junction proteins, claudin-1, claudin-3, hemorrhagic stroke, seizures, neuroinflammation
MeSH terms
Adult, Aged, Animals, Ataxia, Basal Ganglia, Blood-Brain Barrier, Brain, Cerebral Hemorrhage, Crosses, Genetic, Female, Gene Expression Regulation, Homeostasis, Humans, Hyperesthesia, Inflammation, Male, Mice, Transgenic, Middle Aged, Organ Specificity, Seizures, Down-Regulation, Cytokines, Genes, Reporter, Transgenes, Tight Junctions, RNA Interference, Endothelial Cells, beta Catenin, Mice, Gene Knockdown Techniques, Claudin-1, Claudin-3

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