{"doi":"10.1016/j.redox.2025.103876","title":"Glypican 1 mechanosensing mediates eNOS uncoupling during hydrostatic pulmonary edema","abstract":"Hydrostatic pulmonary edema is a life-threatening condition caused by an acute increase in pulmonary capillary pressure. The molecular mechanisms whereby hydrostatic pulmonary edema develops are unresolved. The pulmonary endothelial glycocalyx is a mechano-sensitive signaling layer known to regulate lung endothelial permeability. Within the glycocalyx, membrane-bound heparan sulfate proteoglycans (HSPGs) are putative mechano-sensors. Herein, investigated if the membrane-bound HSPG glypican 1 is a mechanosensor in the lung vasculature and its role in hydrostatic pulmonary edema progression. Using an isolated perfused lung system, we showed that glypican 1 knockout mice ( Gpc1 -/- ) are protected from pressure-induced lung edema, a phenotype associated with impaired dextran 70KDa transport and decreased reactive oxygen species (ROS) production. Using wild-type (WT) mouse lung endothelial cells (MLEC) and human lung microvascular endothelial cells (HLMEC), we show that high pressure induces the activation of Protein Kinase C-alpha (PKCα) at Y 657 , which phosphorylates endothelial nitric oxide synthase (eNOS) at T 495 . This is associated with increased ROS production by eNOS-dependent pathways. The inhibition of eNOS with ethyl thiourea (ETU) or N5-(1-iminoethyl)-l-ornithine (L-NIO) mitigates the effects of high pressure on ROS production, lung edema, and barrier stability. This pathologic signaling axis is not activated in Gpc1 -/- MLEC exposed to high-pressure conditions. Notably, cells deficient in Glypican 1 show increased phosphorylation of PKCα at T 638 , a site associated with PKCα stability and inactivation. The protective signaling mechanisms observed in Gpc1 -/- MLEC are replicated in HLMEC silenced for glypican 1, supporting a conserved role for glypican 1 in barrier function across species. In conclusion, we show that glypican 1 is a mechanosensor in the lung vasculature that mediates the effects of high pressure on barrier function by redox-sensitive pathways. This may be important for the progression of hydrostatic pulmonary edema in humans. Therapies targeting glypican 1 may be novel strategies to treat hydrostatic pulmonary edema.","journal":"Redox Biology","year":2025,"id":547062,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9517,"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":1439489,"name":"Joaquín Rosales","orcid":null,"position":1,"is_corresponding":false},{"id":734044,"name":"Ayman Isbatan","orcid":"0000-0003-1663-3606","position":2,"is_corresponding":false},{"id":231631,"name":"Christian Bime","orcid":"0000-0003-4787-2685","position":3,"is_corresponding":false},{"id":703607,"name":"João L. Carvalho-de-Souza","orcid":"0000-0003-3231-0436","position":4,"is_corresponding":false},{"id":734046,"name":"Randal O. Dull","orcid":"0000-0003-4202-2286","position":5,"is_corresponding":false},{"id":227887,"name":"Stephen M. Black","orcid":"0000-0002-4524-6544","position":6,"is_corresponding":false},{"id":734047,"name":"Andréia Z. Chignalia","orcid":"0000-0002-3220-0942","position":7,"is_corresponding":false},{"id":1439488,"name":"Lakshmi Narasimha Rao Thota","orcid":null,"position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T02:53:36.567932Z","pmid":"41016239","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":[]}