{"doi":"10.1101/2025.10.24.683742","title":"Piezo1 Triggers an Angiopoietin-2-Integrin Signaling Loop in Schlemm’s Canal to Regulate Intraocular Pressure","abstract":"Abstract Elevated intraocular pressure (IOP), driven by increased outflow resistance in the trabecular meshwork and Schlemm’s 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 α9β1 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 α9β1. 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":579068,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9605,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":274700,"name":"Dilip K. Deb","orcid":"0000-0001-6720-8517","position":1,"is_corresponding":false},{"id":1191114,"name":"Hongyuan Ren","orcid":"0009-0006-6653-4031","position":2,"is_corresponding":false},{"id":1489714,"name":"Kerolous Salama","orcid":null,"position":3,"is_corresponding":false},{"id":283288,"name":"Yalu Zhou","orcid":null,"position":4,"is_corresponding":false},{"id":816852,"name":"Haiyan Gong","orcid":"0000-0002-7204-5019","position":5,"is_corresponding":false},{"id":630502,"name":"Benjamin R. Thomson","orcid":"0000-0001-6565-5866","position":6,"is_corresponding":false},{"id":245996,"name":"Susan E. Quaggin","orcid":"0000-0002-3706-5727","position":7,"is_corresponding":false},{"id":1302431,"name":"Naoki Kiyota","orcid":"0000-0003-4613-7048","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:58:30.282164Z","pmid":"41279337","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}