Mediating effects of aryl-hydrocarbon receptor and RhoA in altering brain vascular integrity: the therapeutic potential of statins.
We have demonstrated previously that focal adhesion kinase (FAK)/RhoA alteration by the aryl-hydrocarbon receptor (AhR) agonist 3-methylcholanthrene (3MC) is involved in the antimigratory effects of 3MC in human umbilical vascular endothelial cells. Here, we identified that signaling properties and molecular mechanisms of RhoA/β-catenin were both implicated in alterations to blood-brain ... barrier integrity. The mechanisms of action were the down-regulation of integrin, the extracellular matrix, and adherens junction stability. PTEN phosphorylation by 3MC-mediated AhR/RhoA activation increased the proteasomal degradation of β-catenin through PKCδ/pGSK3β-mediated β-catenin phosphorylation; the crucial roles of AhR/RhoA in this process were verified by using gain- or loss-of-function experiments. The decrease in β-catenin led to decreased expression of fibronectin and α5β1 integrin. Additionally, protein interactions among FAK, VE-cadherin, vinculin, and β-actin were simultaneously decreased, resulting in adherens junction instability. Novel functional TCF/LEF1 binding sites in the promoter regions of fibronectin and α5/β1 integrin were identified by electrophoretic mobility shift and chromatin immunoprecipitation assays. The results indicate that the binding activities of β-catenin decreased in mouse cerebrovascular endothelial cells treated with 3MC. In addition, simvastatin and pravastatin treatment reversed 3MC-mediated alterations in mouse cerebrovascular endothelial cells by RhoA inactivation, and the in vitro findings were substantiated by an in vivo blood-brain barrier assay. Thus, endothelial barrier dysfunction due to 3MC occurs through AhR/RhoA-mediated β-catenin down-regulation, which is reversed by simvastatin treatment in vivo.
Mesh Terms:
Animals, Blood-Brain Barrier, Brain, Cells, Cultured, Cerebrovascular Circulation, Drug Evaluation, Preclinical, Endothelium, Vascular, Fibronectins, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Integrin alpha5beta1, Male, Methylcholanthrene, Mice, Mice, Inbred BALB C, PTEN Phosphohydrolase, Phosphorylation, Protein Binding, Receptors, Aryl Hydrocarbon, beta Catenin, rho GTP-Binding Proteins
Animals, Blood-Brain Barrier, Brain, Cells, Cultured, Cerebrovascular Circulation, Drug Evaluation, Preclinical, Endothelium, Vascular, Fibronectins, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Integrin alpha5beta1, Male, Methylcholanthrene, Mice, Mice, Inbred BALB C, PTEN Phosphohydrolase, Phosphorylation, Protein Binding, Receptors, Aryl Hydrocarbon, beta Catenin, rho GTP-Binding Proteins
Am. J. Pathol.
Date: Jul. 01, 2012
PubMed ID: 22720799
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