TRPV4-mediated regulation of intraocular pressure and outflow facility in mouse model of glucocorticoid-induced ocular hypertension




Millar, Cameron
Patel, Pinkal
Kasetti, Ramesh
Maddineni, Prabhavathi
Zode, Gulab


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Purpose: Increased intraocular pressure (IOP) due to increased outflow resistance to aqueous humor at the trabecular meshwork (TM) is one of the major risk factor associated with glaucoma. Transient receptor potential channel vanilloid isoform 4 (TRPV4), a polymodal cation-permeable channel, has been implicated in mechanotransduction. Increased IOP and reduced outflow of aqueous humor may compromise the mechanosensory signaling in the trabecular meshwork. We hypothesize a dysfunction in the mechanotransduction pathway in the TM of hypertensive eyes, and propose a physiological role for TRPV4 channels in regulation of IOP and outflow facility. Methods: The effects of TRPV4 activation was studied using recently developed mouse model of glucocorticoid-induced ocular hypertension. 20 mL of 10 mg/mL dexamethasone-21-acetate (Dex-Ac) formulation was administered weekly to both eyes of C57BL/6J mice via periocular conjunctival fornix injections. Ocular hypertensive mice were topically administered 1 mM GSK1016790A (TRPV4 agonist) in one eye and DMSO vehicle in the contralateral eye. The subsequent effect on IOP was recorded 15, 30, and 60 min intervals after the eye drops and weekly in isoflurane anesthetized mice. Outflow facility was further examined in ocular hypertensive mice treated with 1 mM GSK1016790A eye drops 1 hour prior to the measurements. Results: Weekly periocular injections of Dex-Ac showed significant increase in IOP greater than 5 mmHg, when compared to vehicle control (P. In ocular hypertensive mice, topical administration of TRPV4 activator caused significant and sustained decrease in IOP back to baseline levels, when compared to vehicle treated contralateral eyes (P. IOP measurement at different time points following TRPV4 activation showed a rapid effect on IOP within 60 minutes (P. Measurement of outflow facility via the constant-flow infusion method shows a significant increase in outflow facility one hour after topical administration of TRPV4 agonist when compared to the vehicle treated contralateral eyes (P=0.026). Conclusion: Our data provides physiological evidence for the positive effect of TRPV4 activation on IOP and outflow facility. Further work is required to elucidate the underlying molecular mechanisms behind TRPV4-mediated effect on IOP and outflow facility.


Research Appreciation Day Award Winner - 2018 North Texas Eye Research Institute, Graduate Student Poster Award - 3rd Place