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Guorong Li, William M Johnson, Heather Schmitt, Iris D Navarro, Jenny Jingyi Cui, Marybeth Groelle, Haven Roberts, Michael A Hauser, William D Stamer; Role of LOXL1 in conventional outflow function and behavior. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3190. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Exfoliation glaucoma (XFG) is the most common identifiable cause of open-angle glaucoma, accompanied by exfoliation material present in ocular tissues and elevated intraocular pressure (IOP). In genome-wide association studies, variants in the lysyl oxidase like 1 (Loxl1) locus dramatically increase risk of XFG. Loxl1 is a critical crosslinking enzyme for elastin and collagen. The aim of this study is to examine the effects of Loxl1 on IOP, outflow facility, outflow tissue anatomy, plus behavior of conventional outflow tissues in response to pilocarpine in mice.
Mixed background Loxl1+/+,+/-,-/- (2-12 month-old) mice were used. IOP was measured using rebound tonometry. Outflow facility was determined by iPerfusion system. Morphology of iridocorneal angle tissues was monitored by semi-thin sagittal sections in enucleated eyes and SD-OCT in living eyes. Outflow tissue behavior of cannulated living mouse eyes in response to pilocarpine was examined by SD-OCT. Protein levels of elastin, collagen IV, and fibronectin in outflow tissues were determined by immunofluorescence.
Compared to littermate Loxl1+/+ mice (16.8±1.6 mmHg, n=19), IOP was significantly elevated in Loxl1 +/- (17.9±1.4, n=16, p=0.04) and Loxl1-/- mice (19.3±1.7mmHg, n=17, p = 0.00087). Paradoxically, outflow facility was also significantly increased in Loxl1-/- vs. Loxl1+/+ mice (2.93±0.98, n=13 vs. 5.68±1.74 nl/min/mmHg, n=20, p = 0.002), but not in Loxl+/- mice (2.42±0.3 nl/min/mmHg, n=11). Both histological and OCT imaging of Schlemm’s canal (SC) lumen showed dramatically enlarged SC in Loxl1-/- (6.2±1.5-fold and 4.58±0.6-fold, respectively p=0.001) but not Loxl+/- mice (0.32± 0.07 and 1.06±0.1-fold, respectively p=0.67) compared to that in Loxl1+/+ mice. SC lumen of Loxl1-/-mice also displayed an enhanced response to pilocarpine treatment (21.9% ± 9.1% increase compared to pre-treatment). Qualitatively reduced protein levels of elastin, collagen IV and fibronectin were found in Loxl1-/- but not Loxl+/- compared to that in Loxl1+/+ mice.
Loxl1 ablation in mice altered the balance of extracellular matrix components in the conventional outflow pathway, which appears to cause enlarged SC lumen, enhanced response to pilocarpine, increased outflow facility and ocular hypertension. These results combined with the strong association of LOXL1 locus with XFG, point to a central role for Loxl1 in conventional outflow homeostasis.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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