3D traction force microscopy in human trabecular meshwork tissues: Effects of ROCK and YAP/TAZ inhibition in normal...

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide, with an estimated 112 million people projected to be affected by 2040. The primary risk factor for POAG is elevated intraocular pressure (IOP), which is primarily driven by increased resistance to aqueous humor outflow through the conventional outflow pathway. Despite its prevalence, the precise biomechanical mechanisms underlying this resistance remain unclear. In this study, we utilized 3D in situ traction force microscopy to investigate the effects of the rho kinase (ROCK) inhibitor Y-27632 and the YAP/TAZ inhibitor Verteporfin treatments on the trabecular meshwork (TM) and juxtacanalicular tissue (JCT) cellular contractility and their extracellular matrix (ECM) reorganization in both normal and glaucomatous human donor eyes. Our analysis revealed dysregulated traction forces within glaucomatous tissues, leading to significant ECM reorganization that may contribute to disrupting the homeostasis of the aqueous outflow pathway. Treatments appear to help restore normal ECM structure by adjusting cellular forces. The effect on contractile forces differed between genders, suggesting the significance of gender in treatment response. Our results suggest that targeting these biomechanical pathways may offer new therapeutic strategies to reduce outflow resistance, laying the groundwork for future therapies aimed at preserving vision by restoring ECM biomechanics and improving outflow.