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However, questions remain about how heme\u2010NO signals across the cell membrane. Herein, we test the hypothesis that extracellular heme\u2010NO signals as a nitrodilator that vasodilates by mobilizing NO moiety from a nitrodilator\u2010activated intracellular NO store (NANOS) in the vasculature. We identify a novel mechanism for glutathione\u2010catalyzed formation of a model compound, alb\u2010heme\u2010NO, and determine glutathione (GSH) as a ligand in its structure. Heme\u2010NO complexes with plasma proteins in blood and, as such, it is impermeable to red blood cells or the vascular wall. Alb\u2010heme\u2010NO\u2010mediated vasodilation, both ex vivo and in vivo, is attenuated by prior depletion of the NANOS and potentiated by NANOS supplementation. Incubation with alb\u2010heme\u2010NO 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\u2010NO functions as an extracellular nitrodilator via activation of the intracellular NANOS.<\/jats:p>","DOI":"10.1002\/advs.202516857","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T20:09:02Z","timestamp":1778270942000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Heme\u2010NO Dilates Arteries via Mobilization of NO Moieties From an Intracellular NO Store Within Vascular Smooth Muscle Cells"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1451-7951","authenticated-orcid":false,"given":"Taiming","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pediatrics Division of Neonatology Loma Linda University School of Medicine  Loma Linda California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Division of Neonatology Loma Linda University School of Medicine  Loma Linda California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingchao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of California  Riverside USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Ke","sequence":"additional","affiliation":[{"name":"Metabolomics Core Facility University of California  Riverside USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amancio","family":"de Souza","sequence":"additional","affiliation":[{"name":"Metabolomics Core Facility University of California  Riverside USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicine Gregory Fleming James Cystic Fibrosis Research Center University of Alabama at Birmingham  Birmingham USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Castella","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolai","family":"Lehnert","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lubo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Lawrence D. 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