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@ARTICLE{Kim:128686,
      author       = {J. Kim and D.-Y. Park and H. Bae and D. Y. Park and D. Kim
                      and C.-K. Lee and S. Song and T.-Y. Chung and D. H. Lim and
                      Y. Kubota and Y.-K. Hong and Y. He and H. Augustin$^*$ and
                      G. Oliver and G. Y. Koh},
      title        = {{I}mpaired angiopoietin/{T}ie2 signaling compromises
                      {S}chlemm's canal integrity and induces glaucoma.},
      journal      = {The journal of clinical investigation},
      volume       = {127},
      number       = {10},
      issn         = {1558-8238},
      address      = {Ann Arbor, Mich.},
      publisher    = {ASCJ},
      reportid     = {DKFZ-2017-04701},
      pages        = {3877 - 3896},
      year         = {2017},
      note         = {DKFZ-ZMBH-Allianz},
      abstract     = {Primary open-angle glaucoma (POAG) is often caused by
                      elevated intraocular pressure (IOP), which arises due to
                      increased resistance to aqueous humor outflow (AHO). Aqueous
                      humor flows through Schlemm's canal (SC), a lymphatic-like
                      vessel encircling the cornea, and via intercellular spaces
                      of ciliary muscle cells. However, the mechanisms underlying
                      increased AHO resistance are poorly understood. Here, we
                      demonstrate that signaling between angiopoietin (Angpt) and
                      the Angpt receptor Tie2, which is critical for SC formation,
                      is also indispensable for maintaining SC integrity during
                      adulthood. Deletion of Angpt1/Angpt2 or Tie2 in adult mice
                      severely impaired SC integrity and transcytosis, leading to
                      elevated IOP, retinal neuron damage, and impairment of
                      retinal ganglion cell function, all hallmarks of POAG in
                      humans. We found that SC integrity is maintained by
                      interconnected and coordinated functions of Angpt-Tie2
                      signaling, AHO, and Prox1 activity. These functions diminish
                      in the SC during aging, leading to impaired integrity and
                      transcytosis. Intriguingly, Tie2 reactivation using a Tie2
                      agonistic antibody rescued the POAG phenotype in
                      Angpt1/Angpt2-deficient mice and rejuvenated the SC in aged
                      mice. These results indicate that the Angpt-Tie2 system is
                      essential for SC integrity. The impairment of this system
                      underlies POAG-associated pathogenesis, supporting the
                      possibility that Tie2 agonists could be a therapeutic option
                      for glaucoma.},
      keywords     = {ANGPT1 protein, human (NLM Chemicals) / ANGPT2 protein,
                      human (NLM Chemicals) / Angiopoietin-1 (NLM Chemicals) /
                      Angiopoietin-2 (NLM Chemicals) / Angpt1 protein, mouse (NLM
                      Chemicals) / Homeodomain Proteins (NLM Chemicals) / Tumor
                      Suppressor Proteins (NLM Chemicals) / prospero-related
                      homeobox 1 protein (NLM Chemicals)},
      cin          = {A190},
      ddc          = {610},
      cid          = {I:(DE-He78)A190-20160331},
      pnm          = {311 - Signalling pathways, cell and tumor biology
                      (POF3-311)},
      pid          = {G:(DE-HGF)POF3-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28920924},
      pmc          = {pmc:PMC5617682},
      doi          = {10.1172/JCI94668},
      url          = {https://inrepo02.dkfz.de/record/128686},
}