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A leading cause of blindness worldwide, glaucoma is often caused by elevated intraocular pressure (IOP) due to impaired aqueous humor outflow from the anterior chamber through Schlemm's canal (SC) and the trabecular meshwork. Despite the large clinical burden, glaucoma research and drug development are hindered by a limited selection of preclinical models that accurately recapitulate human disease. Here, we propose that Angpt1 conditional knockout mice may provide one such model. Angiopoietin/TEK (ANGPT/TEK) signaling is crucial for SC formation and integrity in mice and humans, and mice lacking TEK or its ligand ANGPT1 develop a hypomorphic SC insufficient for normal aqueous humor outflow. We used a comprehensive histology and physiology approach to characterize the glaucoma phenotype of Angpt1 inducible knockout mice, especially focusing on retina morphology and function. Angpt1 deletion resulted in persistent ocular hypertension beginning in the first month after birth and leading to decreased visual acuity with age due to glaucomatous neuropathy. In the neural retina, we identified marked and specific loss of the retinal ganglion cells, whereas other retinal neurons exhibited largely normal morphology and patterning. Electroretinogram recordings demonstrated reduced scotopic threshold response, further indicating loss of retinal ganglion cell function. These findings highlight the potential of Angpt1 conditional knockout mice as a valuable new glaucoma model. Currently, few reliable, rapid-onset genetic glaucoma models are available, and Angpt1 knockout mice will provide an additional tool for studies of IOP-induced neural damage, mechanisms of disease progression, and novel treatment strategies. Copyright 2020 The Authors.

Citation

Benjamin R Thomson, Marta Grannonico, Feng Liu, Mingna Liu, Parrykumar Mendapara, Ying Xu, Xiaorong Liu, Susan E Quaggin. Angiopoietin-1 Knockout Mice as a Genetic Model of Open-Angle Glaucoma. Translational vision science & technology. 2020 Mar;9(4):16

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PMID: 32818103

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