Impaired angiopoietin/Tie2 signaling compromises Schlemm's canal integrity and induces glaucoma

Jaeryung Kim; Dae-Young Park; Hosung Bae; Do Young Park; Dongkyu Kim; Choong-Kun Lee; Sukhyun Song; Tae-Young Chung; Dong Hui Lim; Yoshiaki Kubota; Young-Kwon Hong; Yulong He; Hellmut G. Augustin; Guillermo Oliver; Gou Young Koh

doi:10.1172/JCI94668

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Impaired angiopoietin/Tie2 signaling compromises Schlemm's canal integrity and induces glaucoma

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Impaired angiopoietin/Tie2 signaling compromises Schlemm's canal integrity and induces glaucoma

Jaeryung Kim, Dae-Young Park, Hosung Bae, Do Young Park, Dongkyu Kim, Choong-Kun Lee, Sukhyun Song, Tae-Young Chung, Dong Hui Lim, Yoshiaki Kubota, …

The Journal of clinical investigation, Vol.127(10), pp.3877-3896

10/01/2017

DOI: 10.1172/JCI94668

PMID: 28920924

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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.

Life Sciences & Biomedicine

Medicine, Research & Experimental

Research & Experimental Medicine

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Title: Subtitle: Impaired angiopoietin/Tie2 signaling compromises Schlemm's canal integrity and induces glaucoma
Creators: Jaeryung Kim - Korea Advanced Institute of Science and Technology
Dae-Young Park - Korea Advanced Institute of Science and Technology
Hosung Bae - Korea Advanced Institute of Science and Technology
Do Young Park - Korea Advanced Institute of Science and Technology
Dongkyu Kim - Institute for Basic Science
Choong-Kun Lee - Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon, South Korea
Sukhyun Song - Institute for Basic Science
Tae-Young Chung - Samsung Medical Center
Dong Hui Lim - Samsung Medical Center
Yoshiaki Kubota - Keio University
Young-Kwon Hong - University of Southern California
Yulong He - Soochow University
Hellmut G. Augustin - German Cancer Research Center
Guillermo Oliver - Northwestern University
Gou Young Koh - Korea Advanced Institute of Science and Technology
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.127(10), pp.3877-3896
DOI: 10.1172/JCI94668
PMID: 28920924
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: Amer Soc Clinical Investigation Inc
Number of pages: 20
Grant note: Ministry of Science and ICT, Republic of Korea IBS-R025-D1-2015 / Institute of Basic Science
Language: English
Date published: 10/01/2017
Academic Unit: Internal Medicine
Record Identifier: 9985217133402771

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