title: Angiopoietin-2-induced blood-brain barrier compromise and increased stroke size are rescued by VE-PTP-dependent restoration of Tie2 signaling.
abstract: The homeostasis of the central nervous system is maintained by the blood-brain barrier (BBB). Angiopoietins (Ang-1/Ang-2) act as antagonizing molecules to regulate angiogenesis, vascular stability, vascular permeability and lymphatic integrity. However, the precise role of angiopoietin/Tie2 signaling at the BBB remains unclear. We investigated the influence of Ang-2 on BBB permeability in wild-type and gain-of-function (GOF) mice and demonstrated an increase in permeability by Ang-2, both in vitro and in vivo. Expression analysis of brain endothelial cells from Ang-2 GOF mice showed a downregulation of tight/adherens junction molecules and increased caveolin-1, a vesicular permeability-related molecule. Immunohistochemistry revealed reduced pericyte coverage in Ang-2 GOF mice that was supported by electron microscopy analyses, which demonstrated defective intra-endothelial junctions with increased vesicles and decreased/disrupted glycocalyx. These results demonstrate that Ang-2 mediates permeability via paracellular and transcellular routes. In patients suffering from stroke, a cerebrovascular disorder associated with BBB disruption, Ang-2 levels were upregulated. In mice, Ang-2 GOF resulted in increased infarct sizes and vessel permeability upon experimental stroke, implicating a role of Ang-2 in stroke pathophysiology. Increased permeability and stroke size were rescued by activation of Tie2 signaling using a vascular endothelial protein tyrosine phosphatase inhibitor and were independent of VE-cadherin phosphorylation. We thus identified Ang-2 as an endothelial cell-derived regulator of BBB permeability. We postulate that novel therapeutics targeting Tie2 signaling could be of potential use for opening the BBB for increased CNS drug delivery or tighten it in neurological disorders associated with cerebrovascular leakage and brain edema.
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Gurnik
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Kavi
authors.initials: K
authors.lastname: Devraj
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Jadranka
authors.initials: J
authors.lastname: Macas
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Maiko
authors.initials: M
authors.lastname: Yamaji
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Starke
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Scholz
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Sommer
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Di Tacchio
authors.affiliation: Department of Neurology, Goethe University Medical School, Frankfurt, Germany.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Vutukuri
authors.affiliation: Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Beck
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.affiliation: Department of Neurology, Goethe University Medical School, Frankfurt, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Foerch
authors.affiliation: Department of Neurology, Goethe University Medical School, Frankfurt, Germany.
authors.forename: Waltraud
authors.initials: W
authors.lastname: Pfeilschifter
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebner
authors.affiliation: Aerpio Therapeutics, Cincinnati, OH, USA.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Peters
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany.|Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK RheinMain), Frankfurt, Germany.
authors.forename: Karl H
authors.initials: KH
authors.lastname: Plate
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Medical School, Frankfurt, Germany. yvonne.reiss@kgu.de.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Reiss
mesh_terms: D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D001929:Brain Edema / Q000209:etiology / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D017097:Electric Impedance; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D055806:Microvessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D042787:Receptor, TIE-2 / Q000378:metabolism*; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D020521:Stroke / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*
chemical_list: D042702:Angiopoietin-2; D009419:Nerve Tissue Proteins; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3
keywords: Angiopoietin-2; Blood–brain barrier (BBB); Endothelium; Permeability; Stroke; Tie2 signaling; Vascular endothelial protein tyrosine phosphatase (VE-PTP)