TRPV4 controls circadian and pathological ocular hypertension

Area of Science:

• Ophthalmology
• Mechanobiology
• Physiology

Background:

• Ocular hypertension (OHT) involves mechanical stress and glucocorticoids, impacting conventional outflow pathway permeability and vision.
• Physiological nightly intraocular pressure (IOP) elevations in healthy individuals do not cause adverse effects, unlike pathological OHT.
• Mechanosensation's role in regulating physiological versus pathological OHT and its effect on trabecular meshwork (TM) permeability remains unclear.

Purpose of the Study:

• To investigate the role of mechanosensation, specifically transient receptor potential vanilloid isoform 4 (TRPV4), in regulating ocular hypertension (OHT).
• To determine how TRPV4 activation or inhibition affects intraocular pressure (IOP) and trabecular meshwork (TM) outflow facility.
• To explore TRPV4 as a potential therapeutic target for glaucoma.

Main Methods:

• Utilized wild-type mice and conventional outflow-specific Trpv4 knockdown models.
• Administered TRPV4 agonists (GSK1016790A) and antagonists (HC-067047, GSK2193874) topically and via intracameral injection.
• Induced OHT using iridocorneal angle occlusion, dexamethasone treatment, and polystyrene microbeads.
• Assessed IOP, outflow facility in 3-D nanoscaffolds, and retinal neuron protection.

Main Results:

• TRPV4 activation was required for OHT induced by circadian rhythm, angle occlusion, and glucocorticoids.
• TRPV4 agonists lowered IOP when applied topically but elevated it with intracameral injection.
• TRPV4 antagonists reduced IOP in nocturnal OHT, dexamethasone-treated, and microbead-injected eyes.
• Trpv4 knockdown lowered IOP in occluded eyes and protected retinal neurons.
• TRPV4 inhibition increased outflow facility in a biomimetic TM model.

Conclusions:

• Tonic TRPV4 signaling in the TM drives increased outflow resistance, contributing to OHT.
• TRPV4 is essential for maintaining OHT under physiological and pathological conditions mimicking glaucoma.
• Targeting TRPV4 presents a novel therapeutic strategy for controlling IOP in glaucoma.