Biomechanical, ultrastructural, and electrophysiological characterization of the non-human primate experimental glaucoma model

Abstract

Laser-induced experimental glaucoma (ExGl) in non-human primates (NHPs) is a common animal model for ocular drug development. While many features of human hypertensive glaucoma are replicated in this model, structural and functional changes in the unlasered portions of trabecular meshwork (TM) of laser-treated primate eyes are understudied. We studied NHPs with ExGl of several years duration. As expected, ExGl eyes exhibited selective reductions of the retinal nerve fiber layer that correlate with electrophysiologic measures documenting a link between morphologic and elctrophysiologic endpoints. Softening of unlasered TM in ExGl eyes compared to untreated controls was observed. The degree of TM softening was consistent, regardless of pre-mortem clinical findings including severity of IOP elevation, retinal nerve fiber layer thinning, or electrodiagnostic findings. Importantly, this softening is contrary to TM stiffening reported in glaucomatous human eyes. Furthermore, microscopic analysis of unlasered TM from eyes with ExGl demonstrated TM thinning with collapse of Schlemm’s canal; and proteomic analysis confirmed downregulation of metabolic and structural proteins. These data demonstrate unexpected and compensatory changes involving the TM in the NHP model of ExGl. The data suggest that compensatory mechanisms exist in normal animals and respond to elevated IOP through softening of the meshwork to increase outflow.

Lysophosphatidic Acid and IL-6 Trans-signaling Interact via YAP/TAZ and STAT3 Signaling Pathways in Human Trabecular Meshwork Cells

“…One of the major factors implicated in the pathobiology of the TM associated with increased restriction to aqueous humor and elevated IOP in POAG is aberrant remodeling of the ECM. 13,14,21,[64][65][66] As a part of its diverse normal homeostatic functions, the ECM regulates and sequesters growth or bioactive factors from the extracellular milieu. 67,68 However, this ECM-dependent regulation and sequestration of bioactive factors is impaired in the event of aberrant ECM remod-eling.…”

The relationship between outflow resistance and trabecular meshwork stiffness in mice

“…It is interesting to compare this with the findings of Raghunathan et al . 33 , who observed that the TM was stiffer in lasered regions vs. non-lasered regions. Although they did not provide direct evidence of high or low flow in these regions, it is reasonable to assume that the lasered region had low flow vs. the non-lasered regions.…”

Glaucomatous cell derived matrices differentially modulate non-glaucomatous trabecular meshwork cellular behavior

“…Ocular hypertension has long been associated with changes in the ECM, but few have identified a causal relationship between hypertension and ECM. Using a laser induced model of experimental glaucoma in non-human primates (NHPs), we recently demonstrated that normal animals subjected to prolonged elevated pressure are capable of compensation by remodeling their ECM, even when only one clock hour of the TM was left unlasered [35]. The use of NHPs for mechanistic studies are expensive and practically limiting to dissect the dynamic interactions between cells and their ECM.…”