Scleral hypoxia is a target for myopia control.

Area of Science:

• Ophthalmology
• Molecular Biology
• Genetics

Background:

• Myopia, a leading cause of visual impairment, stems from ocular axis elongation and scleral weakening due to extracellular matrix (ECM) remodeling.
• The specific molecular initiators and signaling pathways driving scleral ECM remodeling in myopia remain largely unidentified.

Purpose of the Study:

• To identify key signaling pathways activated in the sclera during myopia development.
• To investigate the role of hypoxia and related pathways in scleral ECM remodeling and myopia progression.
• To explore potential therapeutic strategies targeting hypoxia for myopia control.

Main Methods:

• Single-cell RNA-sequencing of murine sclera to identify activated pathways.
• Experimental induction of myopia in mice and guinea pigs.
• Analysis of human myopia risk genes and their interaction with hypoxia-inducible factor-1α (HIF-1α) signaling.
• In vitro studies on human scleral fibroblasts under hypoxia.
• Pharmacological intervention with antihypoxia drugs (salidroside, formononetin) and pathway inhibitors.

Main Results:

• Hypoxia-signaling, eIF2-signaling, and mTOR-signaling pathways were activated in myopic sclera.
• A significant portion of human myopia risk genes interact with the HIF-1α signaling pathway.
• Experimental myopia induced HIF-1α up-regulation in sclera of mice and guinea pigs.
• Hypoxia promoted myofibroblast transdifferentiation and reduced type I collagen in human scleral fibroblasts.
• Antihypoxia drugs inhibited HIF-1α, eIF2α, and mTOR phosphorylation, slowing myopia progression in guinea pigs.
• Inhibition of eIF2α phosphorylation suppressed myopia, while mTOR phosphorylation induced it in normal mice.

Conclusions:

• Hypoxia plays a critical role in scleral ECM remodeling and myopia development.
• The HIF-1α signaling pathway is a key mediator in myopia pathogenesis.
• Targeting hypoxia represents a potential therapeutic avenue for controlling myopia progression.