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bioRxiv · 10.1101/2025.10.24.683742

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

Kiyota, N.·Deb, D. K.·Thomson, B. R.·Quaggin, S. E.
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Abstract

Elevated intraocular pressure (IOP), driven by increased outflow resistance in the trabecular meshwork and Schlemms canal (SC), is a primary risk factor for glaucoma. This resistance is regulated by broadly active endothelial signaling systems such as ANGPT1-TIE2 and by dynamic flow-responsive pathways that remain poorly understood. Here, we identify a previously unrecognized, TIE2-independent, mechanosensitive ANGPT2-integrin 9{beta}1 pathway in the SC endothelium that regulates IOP. In vitro and in vivo, we show that activation of the mechanosensory channel PIEZO1 triggers ANGPT2 secretion and promotes cell-surface clustering of integrin 9{beta}1. Deletion of SC-expressed Piezo1 or Itga9 in mice resulted in SC narrowing, impaired flow-mediated SC endothelial proliferation, IOP elevation and glaucoma. Furthermore, ANGPT2 deficiency or blockade disrupted PIEZO1-induced integrin activation and reduced aqueous humor outflow facility. These findings establish autocrine PIEZO1-ANGPT2-ITGA9 signaling as a link between mechanosensory stimuli, SC structure and IOP regulation, offering promising new targets for glaucoma therapy.

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Kiyota, N., Deb, D. K., Thomson, B. R., Quaggin, S. E.. 2025-10-24. Piezo1 Activates an Autocrine Angiopoietin-2-Integrin Signaling Loop in Schlemm's Canal to Regulate Intraocular Pressure. https://doi.org/10.1101/2025.10.24.683742

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