title: Endothelial β-Catenin Signaling Is Required for Maintaining Adult Blood-Brain Barrier Integrity and Central Nervous System Homeostasis.
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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Khiem A
authors.initials: KA
authors.lastname: Tran
authors.affiliation: 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.).
authors.forename: Xianming
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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.).
authors.forename: Dan
authors.initials: D
authors.lastname: Predescu
authors.affiliation: 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.).
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Huang
authors.affiliation: 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.).
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Machado
authors.affiliation: 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.).
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Göthert
authors.affiliation: 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.).
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
authors.affiliation: 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.).
authors.forename: Tibor
authors.initials: T
authors.lastname: Valyi-Nagy
authors.affiliation: 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.). yyzhao@uic.edu.
authors.forename: You-Yang
authors.initials: YY
authors.lastname: Zhao
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001259:Ataxia / Q000209:etiology; D001479:Basal Ganglia / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000378:metabolism*; D062445:Claudin-1 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D062465:Claudin-3 / Q000096:biosynthesis / Q000235:genetics; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D006706:Homeostasis; D006801:Humans; D006941:Hyperesthesia / Q000209:etiology; D007249:Inflammation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009928:Organ Specificity; D034622:RNA Interference; D012640:Seizures / Q000209:etiology; D019108:Tight Junctions; D019076:Transgenes; D051176:beta Catenin / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*
chemical_list: C568108:CLDN1 protein, human; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D062445:Claudin-1; D062465:Claudin-3; C568113:Cldn1 protein, mouse; C568123:Cldn3 protein, mouse; D016207:Cytokines; D051176:beta Catenin
keywords: blood–brain barrier; brain; cerebrovascular disorders; endothelium; intracranial hemorrhages