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

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.