{"doi":"10.1101/2025.04.22.650128","title":"Heme-NO dilates arteries via mobilization of NO moieties from a vascular intracellular NO store","abstract":"Abstract Nitrosyl heme (heme-NO) has recently emerged as a surrogate signaling entity for nitric oxide (NO). However, questions remain about how heme-NO signals across the cell membrane. Herein, we test the hypothesis that heme-NO signals as a nitrodilator that vasodilates by mobilizing NO moiety from a nitrodilator-activated intracellular NO store (NANOS) in the vasculature. We identify a novel mechanism for glutathione-catalyzed formation of a model compound, alb-heme-NO, and determine glutathione (GSH) as a ligand in its structure. Heme-NO complexes with plasma proteins in blood and, as such, it is impermeable to red blood cells or the vascular wall. Alb-heme-NO-mediated vasodilation, both in vitro and in vivo , is attenuated by prior depletion of the NANOS and potentiated by NANOS supplementation. Incubation with alb-heme-NO induces efflux of NO moieties from arteries. Additionally, the role of nitrosyl hemoglobin (HbNO) in mediating NO bioactivity export from erythrocytes is challenged. In conclusion, heme-NO functions as an extracellular nitrodilator via activation of the intracellular NANOS.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":564777,"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":0.9512,"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":944399,"name":"Meijuan Zhang","orcid":"0000-0002-5375-5349","position":1,"is_corresponding":false},{"id":303372,"name":"Lingchao Zhu","orcid":null,"position":2,"is_corresponding":false},{"id":483220,"name":"Haiyan Ke","orcid":"0000-0001-9365-7922","position":3,"is_corresponding":false},{"id":898787,"name":"Amancio de Souza","orcid":"0000-0001-6447-3905","position":4,"is_corresponding":false},{"id":1468012,"name":"Qian Li","orcid":"0000-0002-6833-5080","position":5,"is_corresponding":false},{"id":1468013,"name":"Daniel G. Castella","orcid":"0009-0009-1396-9527","position":6,"is_corresponding":false},{"id":409835,"name":"Nicolai Lehnert","orcid":"0000-0002-5221-5498","position":7,"is_corresponding":false},{"id":291057,"name":"Li Zhang","orcid":"0000-0002-9386-8938","position":8,"is_corresponding":false},{"id":921866,"name":"Arlin B. Blood","orcid":"0000-0002-4803-5021","position":9,"is_corresponding":false},{"id":154684,"name":"Taiming Liu","orcid":"0000-0003-1451-7951","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T02:56:24.872312Z","pmid":null,"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":[]}