Impaired TRPV4-eNOS signaling in trabecular meshwork elevates intraocular pressure in glaucoma

Area of Science:

• Ophthalmology
• Cell Biology
• Physiology

Background:

• Primary Open Angle Glaucoma (POAG) is a leading cause of irreversible vision loss.
• Trabecular meshwork (TM) dysfunction is linked to elevated intraocular pressure (IOP) in POAG, but mechanisms are unclear.
• Transient Receptor Potential Vanilloid 4 (TRPV4) channels regulate Ca2+ entry and are implicated in cellular function.

Purpose of the Study:

• To investigate the role of TRPV4 channels in human TM cells and their involvement in IOP regulation.
• To explore the link between TRPV4 channel activity, endothelial nitric oxide synthase (eNOS), and IOP in glaucoma.
• To determine if impaired TRPV4-eNOS signaling contributes to TM dysfunction in POAG.

Main Methods:

• Investigated Ca2+ entry via TRPV4 channels in human TM cells under fluid flow.
• Utilized TM-specific TRPV4 knockout mice to assess IOP regulation.
• Examined the effect of pharmacological TRPV4 activation on aqueous humor outflow and IOP in mice.
• Assessed TRPV4-eNOS signaling in TM and Schlemm's canal cells.
• Analyzed TRPV4 channel activity and signaling in glaucomatous human TM cells.

Main Results:

• Direct evidence of Ca2+ entry through TRPV4 channels in human TM cells, activated by fluid flow.
• TM-specific TRPV4 knockout mice exhibited elevated IOP.
• Pharmacological TRPV4 activation lowered IOP and improved outflow facility in mice.
• TRPV4 activated eNOS in TM cells, crucial for IOP reduction; this signaling was more pronounced in TM cells than Schlemm's canal cells.
• Glaucomatous human TM cells displayed impaired TRPV4 activity and disrupted TRPV4-eNOS signaling, with reduced flow/shear stress activation.

Conclusions:

• TRPV4-eNOS signaling plays a critical role in regulating IOP.
• Impaired TRPV4 channel activity in TM cells contributes to TM dysfunction and elevated IOP in POAG.
• Targeting TRPV4 channels may offer a therapeutic strategy for glaucoma.