Angiopoietin-2-induced blood–brain barrier compromise and increased stroke size are rescued by VE-PTP-dependent restoration of Tie2 signaling

Stefanie Gurnik, Kavi Devraj, Jadranka Macas, Maiko Yamaji, Julia Starke, Alexander Scholz, Kathleen Sommer, Mariangela Di Tacchio, Rajkumar Vutukuri, Heike Beck, Michel Mittelbronn, Christian Foerch, Waltraud Pfeilschifter, Stefan Liebner, Kevin G. Peters, Karl H. Plate, Yvonne Reiss*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

92 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)753-773
Number of pages21
JournalActa Neuropathologica
Volume131
Issue number5
DOIs
Publication statusPublished - 1 May 2016
Externally publishedYes

Keywords

  • Angiopoietin-2
  • Blood–brain barrier (BBB)
  • Endothelium
  • Permeability
  • Stroke
  • Tie2 signaling
  • Vascular endothelial protein tyrosine phosphatase (VE-PTP)

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