Outflow Facility in Mice with a Targeted Type I Collagen Mutation

Dai, Yi; Lindsey, James D.; Duong-Polk, Xuandao T.; Nguyen, Duy Duc; Hofer, Anthony; Weinreb, Robert N.

doi:10.1167/iovs.08-3367

Cited by 28 publications

(22 citation statements)

References 24 publications

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“…This decrease in aqueous outflow facility in eyes perfused at 50 mm Hg was evident from the first hour and persisted till the 4 th hour post baseline perfusion, indicating increased resistance to aqueous outflow in response to elevated perfusion pressure. This observation was found to be consistent with several previous reports in which an inverse association has been confirmed between IOP and AH outflow facility (Battista et al, 2008; Becker and Constant, 1956; Brubaker, 1975; Dai et al, 2009; Hashimoto and Epstein, 1980). These data also indicate that under conditions of acutely increased perfusion pressure, the AH outflow tissues appear to adapt to facilitate increased AH drainage through the conventional pathway within the first hour, based on the observed increase in the aqueous outflow rate in the eyes perfused at 50 mm Hg.…”

supporting

confidence: 93%

Elevated intraocular pressure induces Rho GTPase mediated contractile signaling in the trabecular meshwork

Pattabiraman

Inoue

Rao

2015

Experimental Eye Research

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Rho GTPase regulated contractile signaling in the trabecular meshwork (TM) has been shown to modulate aqueous humor (AH) outflow and intraocular pressure (IOP). To explore whether elevated IOP, a major risk factor for primary open angle glaucoma (POAG) influences Rho GTPase signaling in the TM, we recorded AH outflow in enucleated contralateral porcine eyes perfused for 4–5 hours at either 15 mm or 50 mm Hg pressure. After perfusion, TM tissue extracted from perfused eyes was evaluated for the activation status of Rho GTPase, myosin light chain (MLC), myosin phosphatase target substrate 1 (MYPT1), myristoylated alanine-rich C-kinase substrate (MARCKS) and paxillin. Eyes perfused at 50 mm Hg exhibited a significant decrease in AH outflow facility compared with those perfused at 15 mm Hg. Additionally, TM tissue from eyes perfused at 50 mm Hg revealed significantly increased levels of activated RhoA and phosphorylated MLC, MYPT1, MARCKS and paxillin compared to TM tissue derived from eyes perfused at 15 mm Hg. Taken together, these observations indicate that elevated IOP-induced activation of Rho GTPase-dependent contractile signaling in the TM is associated with increased resistance to AH outflow through the trabecular pathway, and demonstrate the sensitivity of Rho GTPase signaling to mechanical force in the AH outflow pathway.

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supporting

confidence: 93%

Elevated intraocular pressure induces Rho GTPase mediated contractile signaling in the trabecular meshwork

Pattabiraman

Inoue

Rao

2015

Experimental Eye Research

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“…Spontaneous glaucoma in the DBA/2J mouse has been a useful model, but to study the importance of other genetic influences using knockout or gene-modified strains, cross-breeding with DBA/2J is needed. The spontaneous glaucoma, collagen 1 deficient mice were recently re-derived to improve breeding efficiency (Dai et al, 2009). Our bead and viscoelastic method is a modification of that reported by Sappington et al (2010), designed to avoid a problem we had with bead reflux when the injection cannula was removed.…”

Section: Discussionmentioning

confidence: 99%

Differential susceptibility to experimental glaucoma among 3 mouse strains using bead and viscoelastic injection

Cone

Gelman

Son

et al. 2010

Experimental Eye Research

149

150

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The purpose of this experiment was to test the susceptibility to retinal ganglion cell (RGC) axon loss and RGC layer cell loss from experimental glaucoma among 3 mouse strains, and between younger and older mice. We obstructed the mouse aqueous outflow channels by injecting 2 μL of 6 μm diameter, polystyrene beads followed by 3 μL of viscoelastic solution into the anterior chamber with a glass micropipette. We evaluated intraocular pressure (IOP) and damage to RGC as measured by optic nerve axon counts and RGC layer neuron counts in 3 strains of young mice (2 month old C57BL/ 6, DBA/2J, and CD1) and 10 month C57BL/6 mice. Bead and viscoelastic injection produced IOP elevation at ≥1 time point in 94.1% of eyes (112/119), with mean IOP difference from fellow eyes of 4.4 ± 3.0 mmHg. By 6-12 weeks, injected eyes were 10.8% longer and 7.6% wider (p <0.0001). Young DBA/2J and C57BL/6 eyes increased axial length significantly more than young CD1 or older C57BL/6 (all p ≤0.02). RGC layer and axon loss was greatest in CD1 mice, significantly more than the other groups (p from 0.04 to <0.0001). Young C57BL/6 eyes elongated more and lost more RGC layer cells than older C57BL/6 mice (p =0.02 and 0.01, respectively). With this mouse glaucoma model, there was differential susceptibility to ocular elongation and RGC layer and axon damage among mouse strains and by age. Factors that determine sensitivity to RGC injury can be studied using transgenic mouse strains with inducible models.

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“…52,53 This has been attributed to an age-dependent accumulation of collagen I in the outflow pathways, due to inhibition of fibrillar collagen turnover, and a reduced outflow facility is found in these mice. 52,54 Taken together, disruption of collagen fibers in the trabecular meshwork may decrease tissue elasticity, alter the shape and cytoskeletal organization of trabecular meshwork cells, and affect expansion–recoil of the trabecular spaces, leading to a compromised aqueous humor outflow and disturbed IOP homeostasis. Of note, a coinvolvement of trabecular and uveoscleral outflow pathways seems plausible, as the observed imbalance of collagen turnover in both these tissues will impede aqueous humor outflow via either route.…”

Section: Discussionmentioning

confidence: 99%

“…Of note, a coinvolvement of trabecular and uveoscleral outflow pathways seems plausible, as the observed imbalance of collagen turnover in both these tissues will impede aqueous humor outflow via either route. 54 …”

Section: Discussionmentioning

confidence: 99%

Aberrant Collagen Composition of the Trabecular Meshwork Results in Reduced Aqueous Humor Drainage and Elevated IOP in MMP-9 Null Mice

Groef

Andries

Siwakoti

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PurposeHomeostatic turnover of the trabecular meshwork extracellular matrix (ECM) is essential to regulate aqueous humor outflow and to maintain intraocular pressure homeostasis. In this study, we evaluated aqueous humor turnover, intraocular pressure, and trabecular meshwork organization in MMP-9 null mice.MethodsIntraocular pressure and aqueous humor turnover were measured in MMP-9 null versus wild-type mice. Morphology of the anterior segment of the eye, with special attention to the structural organization of the trabecular meshwork, was investigated by means of optical coherence tomography, light microscopy, and transmission electron microscopy. Furthermore, using quantitative real-time polymerase chain reaction and immunostainings, we evaluated the ECM composition of the trabecular meshwork. Finally, the integrity and function of the retina and optic nerve were assessed, via optical coherence tomography, histologic techniques, and optomotor testing.ResultsMMP-9 null mice displayed early-onset ocular hypertension and reduced aqueous humor turnover. While transmission electron microscopic analysis did not reveal any abnormalities in the cellular organization of the trabecular meshwork, detailed investigation of collagen expression indicated that there is an aberrant trabecular meshwork ECM composition in MMP-9 null mice. Notably, at the age of 13 months, no glaucomatous neurodegeneration was seen in MMP-9 null mice.ConclusionsOur observations corroborate MMP-9 as an important remodeler of the collagenous composition of the trabecular meshwork and provide evidence for a causal link between MMP-9 deficiency, trabecular meshwork ultrastructure, and ocular hypertension.

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Outflow Facility in Mice with a Targeted Type I Collagen Mutation

Cited by 28 publications

References 24 publications

Elevated intraocular pressure induces Rho GTPase mediated contractile signaling in the trabecular meshwork

Elevated intraocular pressure induces Rho GTPase mediated contractile signaling in the trabecular meshwork

Differential susceptibility to experimental glaucoma among 3 mouse strains using bead and viscoelastic injection

Aberrant Collagen Composition of the Trabecular Meshwork Results in Reduced Aqueous Humor Drainage and Elevated IOP in MMP-9 Null Mice

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