Cold exposure and glaucoma with intraocular pressure dysregulation in population and experimental studies

Extreme cold exposure is an emerging climate-related stressor, but its impact on glaucoma-related outcomes and intraocular pressure (IOP) remains unclear. We conducted an integrated epidemiological and experimental study combining a time-stratified case-crossover analysis of 4090 glaucoma patients in Shanghai with multivariable linear regression and mechanistic experiments. Extreme cold exposure was associated with increased glaucoma outpatient visits, and lower ambient temperature was associated with higher IOP across multiple lag days after adjustment for demographic, meteorological, and air pollution factors. In vivo, chronic cold exposure (4 °C, 22 h/day, 4 weeks) was associated with sustained IOP elevation and anterior segment changes, accompanied by increased extracellular matrix (ECM) deposition, enhanced trabecular meshwork contractility, and elevated serum glucocorticoid and norepinephrine levels. In vitro, dexamethasone increased α-smooth muscle actin (αSMA) and collagen type I alpha 1 chain (COL1A1), while norepinephrine increased myosin regulatory light chain 2 (MLC2) phosphorylation. Transcriptomic analysis identified 5168 differentially expressed genes enriched in ECM organization, TGF-β signaling, calcium signaling, and cGMP-PKG pathways. In conclusion, extreme cold exposure was associated with glaucoma-related outcomes and IOP elevation, and integrated evidence suggests that cold-related neuroendocrine activation may contribute to extracellular matrix remodeling and trabecular meshwork dysfunction, potentially affecting aqueous humor outflow and IOP regulation.