Piezo1 Activates an Autocrine Angiopoietin-2-Integrin Signaling Loop in Schlemm's Canal to Regulate Intraocular...

Area of Science:

• Ophthalmology
• Cell Biology
• Mechanobiology

Background:

• Intraocular pressure (IOP) is a primary risk factor for glaucoma.
• Dysfunction in Schlemm's canal (SC) endothelium impairs IOP regulation.
• Mechanotransduction pathways are critical for SC endothelial cell function.

Purpose of the Study:

• To identify the molecular mechanisms by which SC endothelial cells sense and respond to mechanical stimuli.
• To elucidate the role of the PIEZO1-ANGPT2-ITGA9-FAK pathway in maintaining IOP homeostasis.
• To explore therapeutic potential for glaucoma targeting this pathway.

Main Methods:

• Pharmacological activation of PIEZO1 using Yoda1 in vitro and in vivo.
• Genetic manipulation: endothelial-specific deletion of Piezo1 and inducible knockout of Itga9 in mice.
• Assessment of SC structure, IOP, retinal ganglion cell survival, and endothelial cell proliferation.

Main Results:

• PIEZO1 activation enhances ITGA9 accumulation and FAK phosphorylation in SC cells.
• In vivo, PIEZO1 activation reduces ANGPT2, increases junctional ITGA9, and phosphorylates FAK and TIE2.
• Loss of Piezo1 or Itga9 leads to SC narrowing, elevated IOP, and retinal ganglion cell loss in mice.

Conclusions:

• A novel cell-autonomous PIEZO1-ANGPT2-ITGA9-FAK pathway regulates SC structure and IOP.
• This pathway links mechanical stimuli to structural adaptation of SC endothelium.
• Targeting this pathway offers a potential therapeutic strategy for glaucoma.