Angiopoietin/Tie2 maintain the flow of Schlemm’s canal
Schlemm’s canal is a lymphatic-like vessel in the eye that is critical for proper drainage of aqueous humor. Glaucoma results from increased intraocular pressure due to decreased aqueous humor outflow from the eye; therefore, strategies to enhance Schlemm’s canal function have potential to relieve glaucoma symptoms. In this episode, Gou Young Koh, Jaeryung Kim, and Dae-Young Park investigate factors that underlie the maintenance and integrity of Schlemm’s’ canal. Their work reveals that that angiopoietin/Tie2 signaling is essential for Schlemm’s canal function and integrity. Importantly, increasing Tie2 activity with an agonist antibody restored Schlemm’s canal function and reduced glaucoma phenotypes in mouse models, suggesting Tie2 activation be further explored as a therapeutic strategy for reducing intraocular pressure.
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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
Copyright © 2020 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)