Trabecular Meshwork

Increased synthesis and deposition of extracellular matrix (ECM) proteins in the trabecular meshwork (TM) is associated with TM dysfunction and intraocular pressure (IOP) elevation in glaucoma. However, it is not understood how ECM accumulation leads to TM dysfunction and IOP elevation. Using a mouse model of glucocorticoid (GC)-induced glaucoma, primary human TM cells and human post-mortem TM tissues, we show that increased ECM accumulation leads to endoplasmic reticulum (ER) stress in the TM. The potent GC, dexamethasone (Dex) increased the secretory protein load of ECM proteins in the ER of TM cells, inducing ER stress. Reduction of fibronectin, a major regulator of ECM structure, prevented ER stress in Dex-treated TM cells. Overexpression of fibronectin via treatment with cellular fibronectin also induced chronic ER stress in primary human TM cells. Primary human TM cells grown on ECM derived from Dex-treated TM cells induced ER stress markers. TM cells were more prone to ER stress from ECM accumulation compared to other ocular cell types. Moreover, increased co-localization of ECM proteins with ER stress markers was observed in human post-mortem glaucomatous TM tissues. These data indicate that ER stress is associated with increased ECM accumulation in mouse and human glaucomatous TM tissues.

It has been suggested that common mechanisms may underlie the pathogenesis of primary open-angle glaucoma (POAG) and steroid-induced glaucoma (SIG). The biomechanical properties (stiffness) of the trabecular meshwork (TM) have been shown to differ between POAG patients and unaffected individuals. While features such as ocular hypertension and increased outflow resistance in POAG and SIG have been replicated in mouse models, whether changes of TM stiffness contributes to altered IOP homeostasis remains unknown. We found that outer TM was stiffer than the inner TM and, there was a significant positive correlation between outflow resistance and TM stiffness in mice where conditions are well controlled. This suggests that TM stiffness is intimately involved in establishing outflow resistance, motivating further studies to investigate factors underlying TM biomechanical property regulation. Such factors may play a role in the pathophysiology of ocular hypertension. Additionally, this finding may imply that manipulating TM may be a promising approach to restore normal outflow dynamics in glaucoma. Further, novel technologies are being developed to measure ocular tissue stiffness in situ. Thus, the changes of TM stiffness might be a surrogate marker to help in diagnosing altered conventional outflow pathway function if those technologies could be adapted to TM.

Polymorphisms in the CAV1/2 genes that encode signature proteins of caveolae are associated with glaucoma, the second leading cause of blindness worldwide, and with its major risk factor, intraocular pressure (IOP). We hypothesized that caveolin-1 (Cav-1) participates in IOP maintenance via modulation of aqueous humor drainage from the eye. We localize caveolae proteins to human and murine conventional drainage tissues and show that caveolae respond to mechanical stimulation. We show that Cav-1-deficient (Cav-1-/-) mice display ocular hypertension explained by reduced pressure-dependent drainage of aqueous humor. Cav-1 deficiency results in loss of caveolae in the Schlemm's canal (SC) and trabecular meshwork. However, their absence did not appear to impact development nor adult form of the conventional outflow tissues according to rigorous quantitative ultrastructural analyses, but did affect cell and tissue behavior. Thus, when IOP is experimentally elevated, cells of the Cav-1-/- outflow tissues are more susceptible to plasma membrane rupture indicating that caveolae play a role in mechanoprotection. Additionally, aqueous drainage from Cav-1-/- eyes was more sensitive to nitric oxide (NO) synthase inhibition than controls, suggesting that excess NO partially compensates for outflow pathway dysfunction. These results provide a functional link between a glaucoma risk gene and glaucoma-relevant pathophysiology.

PurposeTo evaluate the effect of trabecular meshwork strip peeling (TP) during hemi-gonioscopy-assisted transluminal trabeculotomy (hemi-GATT) on the frequency of early postoperative intraocular pressure (IOP) spikes and surgical success.MethodsThis retrospective study included 42 eyes of patients with primary open-angle or pseudoexfoliative glaucoma who underwent hemi-GATT with TP (n = 14) or standard hemi-GATT without TP (n = 28) at a tertiary glaucoma center. Hemi-GATT was intentionally selected as a planned primary surgical strategy and was not performed as a secondary procedure following failed circumferential GATT. An IOP spike was defined as postoperative IOP > 30 mm Hg or an increase of ≥ 10 mm Hg from the previous visit. Surgical success was defined as qualified (IOP ≤ 21 mm Hg and ≥ 30% reduction from baseline with or without medication) or complete (without medication). The primary outcome was the incidence and predictors of early IOP spikes; secondary outcomes included surgical success rates and related risk factors.ResultsAn IOP spike occurred in 11/42 eyes (26.2%) at 7.1 ± 4.8 days postoperatively, lasting 6.7 ± 5.1 days; mean peak IOP during spikes was 26.2 ± 5.0 mm Hg. All patients with an IOP spike experienced a decrease in IOP to ≤ 21 mm Hg within the first postoperative month. Spike frequency was lower with hemi-GATT + TP than with standard hemi-GATT (1/14 [7.1%] vs. 10/28 [35.7%]; p = 0.048). On multivariable analysis, higher baseline IOP increased spike risk (odds ratio [OR], 1.48; 95% CI, 1.08-2.01; P = 0.013), whereas TP reduced it (OR, 0.01; 95% CI, 0.01-0.38; P = 0.014). The mean follow-up period was 7.71 ± 2.03 months (range: 6-13 months). Qualified and complete success did not differ (92.9% vs. 89.3%, P = 0.769; 42.9% vs. 35.7%, p = 0.714).ConclusionTP during hemi-GATT significantly decreases early postoperative IOP spikes and enhances early IOP control, while maintaining surgical success.