Impaired angiopoietin/Tie2 signaling compromises Schlemm’s canal integrity and induces glaucoma
Jaeryung Kim, … , Guillermo Oliver, Gou Young Koh
Jaeryung Kim, … , Guillermo Oliver, Gou Young Koh
Published October 2, 2017; First published September 18, 2017
Citation Information: J Clin Invest. 2017;127(10):3877-3896. https://doi.org/10.1172/JCI94668.
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Categories: Research Article Ophthalmology Vascular biology

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

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.

Authors

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

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Figure 14

Reduced Angpts and Tie2, cellularity, cell-cell junction, and transcytosis in aged SC.

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Reduced Angpts and Tie2, cellularity, cell-cell junction, and transcytos...
(A–E) Images and comparisons of IOP, relative area, number of Erg+ ECs, and intensities of Tie2, p-Tie2, and Prox1 immunostaining in CD144+ SC of 2-month-old versus 18-month-old mice. Dashed lines demarcate the margins of SC. Each area marked by a yellow box is magnified in the top corner. Scale bars: 100 μm; 10 µm (EM). SC area and expression of each molecule in 2-month-old mice are normalized to 100%, and their relative levels in 18-month-old mice are presented. n = 5 for each group. *P < 0.05 versus 2 months by Mann-Whitney U test. (A, F, and G) EM images and comparisons of the number and diameter of GV (blue arrowheads) in the inner SC wall. n = 4 for each group. *P < 0.05 versus 2 months by Mann-Whitney U test. (H) Comparison of Angpt1 and Angpt2 mRNA expression in cornea, limbus, and lung of mice at P7, 2 months, and 18 months of age. Fold changes in mRNA expression relative to the levels of 2-month-old mice are presented. n = 4 for each group. *P < 0.05 by Kruskal-Wallis test followed by Tukey’s HSD test with ranks. (I) Images showing expression of Angpt1, Angpt2, and CD144 in SC and Angpt2 in corneal endothelium. Scale bars: 100 μm.