Eyeworld

EW GLAUCOMA 106 February 2018 in humans Tie2 mutations have been detected in patients with primary congenital glaucoma. 8,9 The role of the Angpt-Tie2 pathway in the functionality of Schlemm's canal into adulthood, however, was un- known prior to Kim et al.'s research. To address this, Kim et al. ob- served expression of Tie2 in normal mice and noted this receptor as well as Prox1, a lymphatic regulator, were detected in the endothelial cells of adult human Schlemm's canal, with expression higher at the inner wall of Schlemm's. In mice, Angpt1 was expressed in pericytes of Schlemm's and Angpt2 was expressed in the trabecular meshwork and corneal endothelium, which Kim et al. said, "implies that Tie2 in the SC is con- stantly exposed to Angpt1 and Angpt2 secreted from the adjacent cells directly or via [aqueous humor]." In older but normal mice, the researchers observed reduced levels of giant vacuoles and decreased ex- pression of Tie2, Angpt1, and Angpt2, and other related proteins, which the investigators wrote correlates with the age-related risk factor of developing glaucoma. This, along with other studies, Drs. Kim and Koh said, suggests the loss of Tie2 signaling underlies age-dependent deterioration of Schlemm's canal function. As Kim et al. put it, "Of importance, Tie2 is highly present in [Schlemm's canal endothelial cells] in adults and supposedly decreases with aging, which is an important risk factor for POAG." The researchers deleted Angpt1, Angpt2, both Angpt1/Angpt2, Tie2, and Prox1 in adult mice in separate tests and evaluated several factors related to Schlemm's canal. Tie2 and Angpt1/Angpt2 deletion (sim- ilar pathogenesis for adult onset primary open angle glaucoma) was found to result in higher intraocular pressures, retinal damage, and some visual impairment. The research- ers noted a decreased number of giant vacuoles in Schlemm's canal endothelial cells, which was related to poor aqueous humor outflow. Deletion of just Angpt1 or Angpt2 did result in mild regression of Schlemm's canal area, but did not significantly elevate IOP. "We note that a more than 50% reduction in SC area and a marked reduction in transcytotic activity in SC ECs are prerequisites for the significant elevation of IOP, retinal neuronal damage, and impairment of retinal ganglion cell function," Kim et al. wrote. The researchers activated Tie2, using an intraocular injection of a Tie2-activating antibody (ABTAA), in mice with Angpt1/Angpt2 deleted and found that it could reduce IOP and recover Schlemm's canal area. In a normal but aged mouse, the same injection was performed in one eye and compared to a control injection in the other eye. IOP and the area of Schlemm's canal were not significantly altered in this case, but the number of giant vacuoles and their diameter were significa- tion increased, as were the levels of Prox1, Tie2, and other factors. This Kim et al. described as its ability to "rejuvenate aged [Schlemm's canal.]" "Angpt-Tie2 system not only maintains Schlemm's canal func- tion, but also has powerful vascu- lar protective effect: suppressing vascular leakage, inhibiting vascular inflammation, and preventing en- dothelial death," Drs. Kim and Koh said. "To overcome limitations of current vascular endothelial growth factor-based anti-angiogenic thera- pies in cancer, wet age-related mac- ular degeneration, and macular ede- ma, drugs that target the Angpt-Tie2 system are in clinical development for ophthalmological and oncolog- ical applications." However, Drs. Kim and Koh noted that Angpt1 and Tie2 have been implicated in vessel remodeling, induction of angiogen- esis, pulmonary hypertension, and venous malformation, indicating the need to minimize these effects while optimizing vessel protection. The ABTAA antibody injected every 3 days in the Park et al. 10 study to activate Tie2 did not show systemic vascular effects. "Considering the potentially decreased Tie2 activity in glaucoma status, we postulate that it is unnec- essary to worry about the side effects of Tie2 activation by ABTAA for glaucoma treatment," they said. Drs. Kim and Koh noted the need for further investigation on the structural integrity and functional- ity of the trabecular meshwork that is secondarily impaired, based on their observations, with Schlemm's canal-associated pathogenesis of primary open angle glaucoma. Drs. Kim and Koh also said it would be interesting to further investigate the mechanism of the unique response of Schlemm's endo- thelial cells to the Angpt-Tie2 system that triggers partial lymphatic endothelial reprogramming of this vascular bed. "In addition, given that sup- plemental VEGFC promotes growth of Schlemm's canal in aged mice and our study shows Tie2 activation rejuvenates aged Schlemm's canal, it is worth identifying a close crosstalk between Angpt-Tie2 signaling and VEGFC-VEGFR3 signaling in delay SC aging," they said. 11 EW References 1. Kim J, et al. Impaired angiopoietin/Tie2 signaling compromises Schlemm's canal integrity and induces glaucoma. J Clin Invest. 2017;127:3877–3896. 2. Park DY, et al. Lymphatic regulator PROX1 determines Schlemm's canal integrity and identity. J Clin Invest. 2014;124:3960–74. 3. Jablonska J, et al. Schlemm's Canal: The Outflow "Vessel." Glaucoma – Intraocular Pressure and Aqueous Dynamics. Dr. Parul Ichhpujani (Ed.), InTech. 2016. 4. Overby DR, et al. Altered mechanobiol- ogy of Schlemm's canal endothelial cells in glaucoma. Proc Natl Acad Sci USA. 2014;111:13876–81. 5. Simon DD, et al. In vitro formation of "giant vacuole-like" structures in Schlemm's canal vs. HUVEC cells. Invest Ophthalmol Vis Sci. 2009;50:4854. 6. Bill A, et al. Scanning electron microscopic studies of the trabecular meshwork and canal of Schlemm—an attempt to localize the main resistance to outflow of aqueous humor in man. Acta Ophthalmol (Copenh). 1972;50:295–320. 7. Johnson M. What controls aqueous humor outflow resistance? Exp Eye Res. 2006;82:545–57. 8. Thomson BR, et al. A lymphatic defect causes ocular hypertension and glaucoma in mice. J Clin Invest. 2014;124:4320–4. 9. Souma T, et al. Angiopoietin receptor TEK mutations underlie primary congenital glau- coma with variable expressivity. J Clin Invest. 2016;126:2575–87. 10. Park JS, et al. Normalization of tumor vessels by Tie2 activation and Ang2 inhibi- tion enhances drug delivery and produces a favorable tumor microenvironment. Cancer Cell. 2016;30:953–967. 11. Aspelund A, et al. The Schlemm's canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel. J Clin Invest. 2014;124:3975–86. Editors' note: Drs. Kim and Koh have no financial interests related to their comments. Contact information Kim: jaeryung502.kim@gmail.com Koh: gykoh@kaist.ac.kr Study continued from page 104 The pathogenesis of glaucoma Sir Peng Khaw, MD, discusses the pathogenesis of glaucoma and research into optic nerve head stem cell transplantation. EWReplay.org

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