Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension

Area of Science:

• Biophysics
• Cell Biology
• Ophthalmology

Background:

• Cholesterol is linked to pressure-related diseases like glaucoma.
• The role of cholesterol in cellular mechanotransduction remains unclear.
• Trabecular meshwork (TM) cells are crucial for regulating intraocular pressure.

Purpose of the Study:

• To investigate the relationship between mechanical strain, membrane cholesterol, and the TRPV4 channel in TM cells.
• To understand how cholesterol affects the mechanosensing properties of TM cells.
• To explore the potential implications for glaucoma and diabetes.

Main Methods:

• Utilized human TM cells subjected to cyclic stretch.
• Manipulated free membrane cholesterol levels using m-β-cyclodextrin (MβCD).
• Assessed TRPV4 channel activation, membrane protein expression, and induced currents in oocytes.

Main Results:

• Cyclic stretch decreased membrane cholesterol/phosphatidylcholine ratio and increased stress fibers.
• Cholesterol depletion augmented TRPV4 activation by agonists and mechanical strain.
• TRPV4 channels were found mainly outside cholesterol-enriched membrane domains.

Conclusions:

• Membrane cholesterol regulates the transduction of mechanical information in TM cells.
• The biomechanical environment influences TM cell membrane lipid composition.
• Modulation of TM mechanosensing by cholesterol may impact intraocular pressure in glaucoma and diabetes.