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

Area of Science:

• Ophthalmology
• Cell Biology
• Mechanobiology

Background:

• Glaucoma is a leading cause of blindness, with elevated intraocular pressure (IOP) as a key modifiable risk factor.
• The trabecular meshwork (TM) is crucial for IOP regulation and is mechanosensitive, but its response to high IOP is not fully understood.

Purpose of the Study:

• To investigate human trabecular meshwork (TM) cell responses to mechanical stimuli and acute ocular hypertension.
• To explore the role of Rap1-YAP1 mechanosignaling in TM cell damage and fibrotic changes.

Main Methods:

• Single-cell sequencing of human TM cells.
• Establishment of in vivo and in vitro models of acute ocular hypertension.
• Analysis of TM cell death, cytoskeletal rearrangement, fibrotic biomarker expression, and YAP1/Rap1 signaling.

Main Results:

• Acute IOP elevation induced TM cell death, cytoskeletal rearrangement, and fibrotic biomarker upregulation in human and mouse models.
• Phosphorylated YAP1 and Rap1 levels were reduced following acute IOP elevation.
• Rap1b knockin mice showed protection against TM damage and YAP1 upregulation after acute IOP elevation.

Conclusions:

• Human TM cells are susceptible to mechanical stress from elevated IOP.
• The Rap1-YAP1 mechanosignaling pathway is implicated in TM cell response to acute IOP elevation.
• Targeting Rap1-YAP1 mechanosignaling may offer a novel therapeutic strategy for protecting the TM in glaucoma.