Targeting Rap1-YAP1 mechanosignaling for ameliorating acute IOP elevation-induced trabecular meshwork dysfunction

Glaucoma is the second leading cause of blindness, and intraocular pressure (IOP) is the principal and only modifiable risk factor. The trabecular meshwork (TM) remains the most important target for IOP regulation; although it is highly mechanosensitive, TM responses to high IOP remain unclear. This study suggested that human TM cells are susceptible to mechanical stimuli using single-cell sequencing; further, in vivo and in vitro models of acute ocular hypertension were established. TM cells underwent significant cell death and cytoskeletal rearrangement after acute IOP elevation. Expression of classic fibrotic biomarkers was significantly upregulated in both mice and human TM cells, whereas levels of phosphorylated YAP1 and Rap1 were reduced. Notably, Rap1b knockin mice exhibited no significant TM death, extracellular matrix disruption, or upregulation of YAP1 following acute IOP elevation. Accordingly, Rap1-YAP1 mechanosignaling might be a novel therapeutic target for TM protection following glaucoma-associated acute IOP elevation.