(OHT) is associated with the activation of the transient receptor potential vanilloid isoform 4 () channel.
TRPV4 is necessary for maintaining ocular hypertension under both normal and disease conditions.
Elevations in intraocular pressure due to factors like iridocorneal angle blockage or steroid use can be inhibited by TRPV4 antagonists.
Activation of TRPV4 can lead to increased resistance to fluid outflow in the eye.
Knocking down TRPV4 in the can prevent ocular hypertension and protect against glaucoma.
These findings suggest that TRPV4 plays a critical role in regulating intraocular pressure and may serve as a potential target for glaucoma therapies.
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(OHT) caused by mechanical stress and chronic glucocorticoid exposure reduces the hydraulic permeability of the conventional outflow pathway and increases the risk for irreversible vision loss, yet healthy individuals experience nightly intraocular pressure (IOP) elevations without adverse lifetime effects. It is not known how mechanosensation regulates physiological vs. pathological OHT nor how it impacts permeability of the principal drainage pathway through the (TM). We report that OHT induced by the circadian rhythm, occlusion of the iridocorneal angle and glucocorticoids requires activation of transient receptor potential vanilloid isoform 4 (), a stretch-activated cation channel. Wild-type mice responded to nocturnal topical administration of the agonist GSK1016790A with IOP lowering, whereas intracameral injection of the agonist elevated diurnal IOP. Microinjection of TRPV4 antagonists HC-067047 and GSK2193874 lowered IOP during the nocturnal OHT phase and in hypertensive eyes treated with dexamethasone or injection of polystyrene microbeads. Conventional outflow-specific Trpv4 knockdown induced partial IOP lowering in mice with an occluded iridocorneal angle and protected retinal neurons from pressure injury. Indicating a central role for TRPV4-dependent mechanosensing in trabecular outflow, HC-067047 doubled the outflow facility in TM-populated steroid-treated 3-D nanoscaffolds. Tonic TRPV4 signalling thus represents a fundamental property of TM biology as a driver of increased in vitro and in vivo outflow resistance. The TRPV4 dependence of OHT under conditions that mimic primary and secondary glaucomas could be explored as a novel target for glaucoma treatments. KEY POINTS: Transient receptor potential vanilloid isoform 4 (TRPV4), a stretch-activated channel, is required to maintain ocular hypertension (OHT) under physiological and pathological conditions. Intraocular pressure elevations induced by occlusion of the iridocorneal angle, administration of steroid eye drops and circadian rhythmicity were blocked by TRPV4 antagonists and mimicked with a TRPV4 agonist. TRPV4 inhibition suppressed steroid-induced increases in outflow resistance in an in vitro biomimetic model of trabecular outflow. Conditional ablation of TRPV4 channels from the trabecular meshwork prevented the induction of OHT and protected the eye from glaucoma. These findings bring physiological and pathological mechanisms that mediate OHT into mechanobiological context and identify a novel target for pressure control in glaucoma.
Key numbers
27.3%
IOP Reduction by Antagonist
Measured decrease in IOP following HC-06 injection during .
25%
Ganglion Cell Loss
Loss of RBPMS cells in peripheral retina of hypertensive wild-type mice.
50%
IOP in Knockout Mice
Comparison of IOP levels in knockout versus wild-type mice.
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