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

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Title
Impaired angiopoietin/Tie2 signaling compromises Schlemm's canal integrity and induces glaucoma
Author(s)
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
Publication Date
2017-10
Journal
JOURNAL OF CLINICAL INVESTIGATION, v.127, no.10, pp.3877 - 3896
Publisher
AMER SOC CLINICAL INVESTIGATION INC
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.
URI
http://pr.ibs.re.kr/handle/8788114/4071
DOI
10.1172/JCI94668
ISSN
0021-9738
Appears in Collections:
Center for Cardiovascular Research(혈관 연구단) > Journal Papers (저널논문)
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