The relationship between outflow resistance and trabecular meshwork stiffness in mice

Abstract

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.

Antifibrotic activity of a rho-kinase inhibitor restores outflow function and intraocular pressure homeostasis

“…TM stiffening and elevated IOP was also observed in animal models of steroid-induced OHT (Raghunathan, Morgan et al 2015, Li, Lee et al 2019. In a recent study, we showed that TM tissue stiffness is associated with increased outflow resistance in steroid-induced OHT mouse eyes (Wang, Li et al 2018). We consider it remarkable that NT appears to have restored normal TM biomechanical properties in our steroid-induced glaucoma model after only 4 days of treatment, and that this restoration was accompanied by significant morphological changes in the extracellular matrix (ECM) of the TM.…”

“…Evidence shows that the biomechanical properties of TM tissue play an important role in the regulation of outflow function, and thus IOP (Wang, Johnstone et al 2017, Wang, Li et al 2018.…”

“…It was desirable to obtain an independent and direct measurement of TM stiffness in a cohort of NT-treated mouse eyes. For this purpose, we used atomic force microscopy (Wang, Read et al 2017, Wang, Li et al 2018, Li, Lee et al 2019. Using the reversal treatment protocol, we observed that NT significantly reduced TM tissue stiffness by 23% compared to contralateral eyes (1.54 ± 0.19 vs. 2.00 ± 0.13 kPa, p = 0.007, Figure 3H).…”

“…Mechanical stiffness of the TM, a key tissue in the conventional outflow pathway, was shown to be increased by GC treatment, negatively correlating with outflow facility (Wang, Li et al 2018).…”

“…Ocular hypertension in mice was created by injection of nanoparticles entrapping dexamethasone (DEX-NPs) into either the subconjunctival or periocular spaces as described in previous publications (Wang, Li et al 2018, Li, Lee et al 2019. Briefly, DEX-NPs were diluted in PBS to a final NP concentration of 50 µg/µl, vortexed for 10 min and then sonicated for 10 min.…”