Abstract
Intraocular pressure (IOP) is the most important risk factor in glaucoma pathogenesis. IOP is regulated by segmental, flow-dependent responses of the inner-wall endothelium of Schlemm's canal (SC), and dysfunction of this system contributes to ocular hypertension and glaucoma. Here, we identify a cell-autonomous PIEZO1-ANGPT2-integrin α9 (ITGA9)-focal adhesion kinase (FAK) mechanotransduction pathway that enables SC endothelial cells to respond to pressure and flow stimuli to maintain IOP homeostasis. Pharmacological activation of the mechanosensitive ion channel PIEZO1 with Yoda1 enhanced ITGA9 accumulation at cell-cell junctions in vitro and induced FAK phosphorylation in an ITGA9- and ANGPT2-dependent manner. In vivo in SC, PIEZO1 activation reduced intracellular ANGPT2, increased junctional ITGA9, and was associated with phosphorylation of FAK and the ANGPT receptor TIE2 (encoded by TEK). Endothelial-specific deletion of Piezo1 or inducible knockout of Itga9 in mice resulted in SC narrowing, elevated IOP, and peripheral retinal ganglion cell loss; double heterozygotes exhibited more severe phenotypes than either single heterozygote, consistent with functional interaction within a single pathway. Moreover, in eyes from Piezo1 and Itga9 mutants, endothelial cell proliferation was reduced, and similar findings have been reported in Angpt2 mutants, supporting a model in which the autocrine flow-PIEZO1-ANGPT2-ITGA9 axis links mechanical stimuli to structural adaptation of SC. These findings suggest that therapeutically targeting this pathway may restore outflow and prevent glaucoma.