Extracellular Matrix Stiffness Modulates Myopia Scleral Remodeling Through Integrin/F-Actin/YAP Axis.

Purpose: Scleral extracellular matrix (ECM) remodeling and weakened scleral stiffness are characteristic of myopia. The purpose of this study was to investigate the precise underlying mechanisms of scleral remodeling regulated by mechanical signals emanating from the ECM. Methods: The expression and regulation of YES-associated protein (YAP) were confirmed in human samples or guinea pig myopia models by Western blot (WB) or ELISA. To mimic the biomechanical microenvironment associated with myopia, stiff (50 kPa) and soft (8 kPa) substrates were established. The underlying mechanisms were further investigated by quantitative real-time RT-PCR, WB, and fluorescence staining in cells treated with siRNAs, plasmids or inhibitors. In vivo, a YAP activator, inhibitor and F-actin polymerization facilitator were applied to evaluate their therapeutic significance for myopia. Results: Our findings revealed that YAP expression is decreased in the sclera of guinea pigs and humans with myopia. Under mechanical stimuli, YAP functions as a mediator, transducing mechanical signals and modulating collagen expression. Furthermore, integrin α1β1 acts as a regulator of YAP and operates through modification of the F-actin cytoskeleton. Specifically, in response to mechanical forces, integrin α1β1 modulates F-actin restructuring. This modified actin cytoskeletal architecture subsequently facilitates the nuclear translocation of YAP, ultimately leading to the suppression of COL1A1 expression. Conclusions: Our results suggest that the integrin α1β1-F-actin-YAP-COL1A1 axis constitutes a vital regulatory mechanism intrinsically associated with the pathogenesis of myopia.