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 17

Schematic diagrams depicting how impairment of Angpt-Tie2 signaling disintegrates the maintenance of SC integrity, leading to glaucomagenesis.

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Schematic diagrams depicting how impairment of Angpt-Tie2 signaling disi...
In normal adult SC, controlled Angpt–Tie2–ERK–Prox1 signaling cascade maintains appropriate AHO and intact GV. On the other hand, in glaucomatous or aged SC, inhibition of Angpt-Tie2 signaling attenuates ERK-Prox1 signaling and subsequently disrupts SC lumen, which consequently leads to decreased AHO. This, in turn, reduces transport of Angpt1 and Angpt2 through AH, resulting in further inhibition of the Angpt-Tie2 system in a vicious cycle manner. These exacerbating processes eventually trigger further disintegration of SC, inducing elevated IOP and accelerating POAG progression. Tie2 activation rejuvenates SC through upregulation of ERK-Prox1 signaling, which promotes AHO while decreasing IOP and eventually prevents POAG progression.