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
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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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 2

Tie2 in the inner SC wall is constantly exposed to Angpts.

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Tie2 in the inner SC wall is constantly exposed to Angpts. (A) Images sh...
(A) Images showing PROX1 and TIE2 in healthy adult human SCs. Scale bars: 100 μm. (B) Cross-section images showing Prox1+ and Tie2+ SC ECs and distribution of collagen IV or PDGFRβ in corneal limbus of 2-month-old Prox1-GFP and Tie2-GFP mice. Dashed arrows indicate direction of AHO. Scale bars: 100 μm. (C) EM images of SC and distribution of PLVAP in the ECs of the inner SC walls in 2-month-old mice. Yellow-lined box is magnified in left lower panel. Blue arrowheads indicate GVs in the inner SC wall, and dashed arrow indicates the direction of AHO. Scale bars: 5 μm (upper panel); 100 μm (right lower panel). (D) Images showing expression of Angpt1 (white arrowheads) in pericytes of SC and Angpt2 in corneal endothelium and TM (black arrowheads) in 2-month-old Angpt1-GFP and Angpt2-lacZ mice. Scale bars: 100 μm. (E) Diagram depicting the sources and distributions of secreted Angpt1 and Angpt2 for the formation and maintenance of Tie2+ SC. CB, ciliary body.