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

Khiem A. Tran, Xianming Zhang, Dan Predescu, Xiaojia Huang, Roberto Machado, Joachim R. Göthert, Asrar B. Malik, Tibor Valyi-Nagy, You Yang Zhao

Research output: Contribution to journalArticle

43 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)177-186
Number of pages10
JournalCirculation
Volume133
Issue number2
DOIs
StatePublished - Jan 12 2016
Externally publishedYes

Fingerprint

Catenins
Blood-Brain Barrier
Homeostasis
Central Nervous System
Endothelial Cells
Claudin-1
Brain
Seizures
Claudin-3
Stroke
Zonula Occludens-1 Protein
Inflammation
Intracranial Hemorrhages
Tight Junctions
Multiple Trauma
Tamoxifen
Down-Regulation
Observation

Keywords

  • blood-brain barrier
  • brain
  • cerebrovascular disorders
  • endothelium
  • intracranial hemorrhages

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Endothelial β-Catenin Signaling Is Required for Maintaining Adult Blood-Brain Barrier Integrity and Central Nervous System Homeostasis. / Tran, Khiem A.; Zhang, Xianming; Predescu, Dan; Huang, Xiaojia; Machado, Roberto; Göthert, Joachim R.; Malik, Asrar B.; Valyi-Nagy, Tibor; Zhao, You Yang.

In: Circulation, Vol. 133, No. 2, 12.01.2016, p. 177-186.

Research output: Contribution to journalArticle

Tran, Khiem A. ; Zhang, Xianming ; Predescu, Dan ; Huang, Xiaojia ; Machado, Roberto ; Göthert, Joachim R. ; Malik, Asrar B. ; Valyi-Nagy, Tibor ; Zhao, You Yang. / Endothelial β-Catenin Signaling Is Required for Maintaining Adult Blood-Brain Barrier Integrity and Central Nervous System Homeostasis. In: Circulation. 2016 ; Vol. 133, No. 2. pp. 177-186.
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