Glaucoma remains one of the leading causes of irreversible vision loss worldwide, and corticosteroid eye drops—used to control inflammation—are known to raise IOP in some patients. Until now, the precise biological trigger for this steroid-induced glaucoma has eluded researchers, leaving ophthalmologists with little guidance beyond tapering or discontinuing the offending medication.
Researchers at Cornell University, led by Esak (Isaac) Lee, PhD, assistant professor of biomedical engineering at Cornell University, have identified the molecular signaling pathway that drives this condition.
Funded by the National Eye Institute, the findings appear in Nature Cardiovascular Research.
Dr. Lee’s group created a 3D “eye-on-a-chip” microphysiological system that reproduces the human eye’s fluid-drainage anatomy with unprecedented fidelity. The platform combines trabecular meshwork (TM) and Schlemm’s canal (SC) cells arranged in a curved, dual-layered structure to mimic the natural outflow pathway for aqueous humor.
When exposed to the steroid dexamethasone, the model revealed a key interaction:
ALK5 receptors in TM cells were activated by the steroid.
This activation downregulated vascular endothelial growth factor C (VEGFC), a protein essential for loosening endothelial junctions in SC cells.
The result was abnormally tightened SC junctions, increased outflow resistance, and elevated IOP.
Mouse studies confirmed the mechanism, firmly linking ALK5/VEGFC signaling to steroid-induced glaucoma.
The research points to two potential therapeutic strategies:
ALK5 Inhibition – Blocking ALK5 signaling could prevent the steroid-driven junction tightening.
VEGFC Supplementation – Delivering VEGFC alongside corticosteroid treatment may maintain normal aqueous humor drainage.
Both approaches hold promise for protecting patients who require long-term steroid therapy yet are vulnerable to glaucoma.
Beyond this discovery, the researchers sayd the eye-on-a-chip system offers a versatile tool for exploring other glaucoma mechanisms and testing targeted interventions. Because the model allows cell-type-specific genetic manipulation, investigators can dissect the roles of individual genes linked to primary open-angle or other glaucoma variants—something difficult to achieve in conventional animal models.