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 September 18, 2017
Citation Information: J Clin Invest. 2017;127(10):3877-3896. https://doi.org/10.1172/JCI94668.
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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 15

Tie2 activation rejuvenates SC in aged mice.

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Tie2 activation rejuvenates SC in aged mice. (A) Diagram depicting the e...
(A) Diagram depicting the experiment schedule in 72-week-old WT mice for intraocular administration of ABTAA (~5 μg, left eye) and Fc (~5 μg, right eye) and analyses 1 week later. (B–G) Images and comparisons of IOP, relative area, number of Erg+ and Ki-67+ ECs, and intensities of Prox1, Tie2, p-Tie2, and Klf4 immunostaining in CD144+ SC. Dashed lines demarcate SC. Scale bars: 100 μm. Area and expression of each molecule in Fc-treated SC are normalized to 100%, and their relative levels of ABTAA-treated SC are presented. n = 4 for each group. *P < 0.05 versus Fc by Mann-Whitney U test. (H–J) EM images and comparisons of the number and diameter of GVs (blue arrowheads) in the inner SC wall. Blue-lined box is magnified in right panel. Red double arrows indicate diameters of GV. Scale bars: 10 μm (left panels); 2 μm (right panels). n = 4 for each group. *P < 0.05 versus Fc by Mann-Whitney U test.