Angiopoietin-1 Regulates Brain Endothelial Permeability through PTPN-2 Mediated Tyrosine Dephosphorylation of Occludin

Blood brain barrier (BBB) breakdown and increased endothelial permeability is a hallmark of neuro-vascular inflammation. Angiopoietin-1 (Ang-1), a Tie-2 receptor agonist ligand, is known to modulate barrier function of endothelial cells; however the molecular mechanisms related to Ang-1 mediated rep...

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Bibliographic Details
Published in:PloS one 2015-06, Vol.10 (6), p.e0130857-e0130857
Main Authors: Siddiqui, M Rizwan, Mayanil, Chandra S, Kim, Kwang Sik, Tomita, Tadanori
Format: Article
Language:English
Subjects:
Angiopoietin
Angiopoietin-1 - metabolism
Angiopoietin-1 - pharmacology
Blood-brain barrier
Blood-Brain Barrier - metabolism
Brain
Brain - metabolism
Brain research
Capillary Permeability - drug effects
Capillary Permeability - genetics
Cell Membrane - metabolism
Confocal microscopy
Dephosphorylation
Edema
Endothelial cells
Endothelial Cells - drug effects
Endothelial Cells - metabolism
Endothelium
Extracellular Signal-Regulated MAP Kinases - metabolism
Gene Deletion
Gene Expression
Homeostasis
Hospitals
Humans
Inflammation
Inflammatory diseases
Intercellular Junctions - drug effects
Intercellular Junctions - metabolism
Ischemia
Kinases
Medicine
Metabolism
Microscopy
Microvasculature
Molecular chains
Molecular modelling
Neurosurgery
Occludin - metabolism
Pediatrics
Permeability
Phenols (Class of compounds)
Phosphatase
Phosphorylation
Protein Transport
Protein Tyrosine Phosphatase, Non-Receptor Type 2 - genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 2 - metabolism
Protein-tyrosine-phosphatase
Proteins
Receptor, TIE-2 - metabolism
siRNA
Thrombin
Thrombin - pharmacology
Tight Junction Proteins - genetics
Tight Junction Proteins - metabolism
Tight junctions
Tyrosine
Vascular endothelial growth factor
Zonula occludens-1 protein
Zonula Occludens-1 Protein - metabolism
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Summary:Blood brain barrier (BBB) breakdown and increased endothelial permeability is a hallmark of neuro-vascular inflammation. Angiopoietin-1 (Ang-1), a Tie-2 receptor agonist ligand, is known to modulate barrier function of endothelial cells; however the molecular mechanisms related to Ang-1 mediated repair of Tight Junctions (TJs) in brain endothelium still remain elusive. In this study, we investigated a novel role of non-receptor protein tyrosine phosphatase N-2 (PTPN-2) in Ang-1 mediated stabilization of tight junction proteins. To study the barrier protective mechanism of Ang-1, we challenged human brain microvascular endothelial cells in-vitro, with a potent inflammatory mediator thrombin. By using confocal microscopy and transwell permeability assay, we show that pretreatment of brain endothelial cells with Ang-1 diminish thrombin mediated disruption of TJs and increase in endothelial permeability. We also found that Ang-1 inhibits thrombin induced tyrosine phosphorylation of Occludin and promote Occludin interaction with Zona Occludens-1 (ZO-1) to stabilize TJs. Interestingly, our study revealed that depletion of PTPN-2 by siRNAs abolishes Ang-1 ability to promote tyrosine dephosphorylation of Occludin, resulting Occludin disassociation from ZO-1 and endothelial hyperpermeability. Collectively, our findings suggest that in brain endothelial cells blocking PTPN-2 mediated tyrosine phosphorylation of Occludin is a novel mechanism to maintain BBB function, and may offer a key therapeutic strategy for neuro-inflammatory disorders associated with BBB disruption.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0130857