biostudies-literatureDurgin BGNIDDK NIH HHSUniversity of PittsburghNHLBI NIH HHSAmerican Heart Association IncNational Institutes of HealthNIH HHS72-80https://www.ebi.ac.uk/biostudies/studies/S-EPMC8766905biostudies-literatureUnknown162Chronic hypoxia is a major driver of cardiovascular complications, including heart failure. The nitric oxide (NO) - soluble guanylyl cyclase (sGC) - cyclic guanosine monophosphate (cGMP) pathway is integral to vascular tone maintenance. Specifically, NO binds its receptor sGC within vascular smooth muscle cells (SMC) in its reduced heme (Fe²⁺) form to increase intracellular cGMP production, activate protein kinase G (PKG) signaling, and induce vessel relaxation. Under chronic hypoxia, oxidative stress drives oxidation of sGC heme (Fe²⁺→Fe³⁺), rendering it NO-insensitive. We previously showed that cytochrome b5 reductase 3 (CYB5R3) in SMC is a sGC reductase important for maintaining NO-dependent vasodilation and conferring resilience to systemic hypertensionJournal of molecular and cellular cardiologySmooth muscle cell CYB5R3 preserves cardiac and vascular function under chronic hypoxic stress.PMC87669051S10OD023684-01A1R01 HL133864F32 HL152498T32 DK007052S10 OD023684F32 HL 152498-0116GRNT27250146R01 HL128304R01 HL 133864DK 007052R01 HL 128304Durgin BGMcMahon BBaust JJStraub ACWood KCHahn SAfalseSmooth muscle cell CYB5R3 preserves cardiac and vascular function under chronic hypoxic stress.Chronic hypoxia is a major driver of cardiovascular complications, including heart failure. The nitric oxide (NO) - soluble guanylyl cyclase (sGC) - cyclic guanosine monophosphate (cGMP) pathway is integral to vascular tone maintenance. Specifically, NO binds its receptor sGC within vascular smooth muscle cells (SMC) in its reduced heme (Fe²⁺) form to increase intracellular cGMP production, activate protein kinase G (PKG) signaling, and induce vessel relaxation. Under chronic hypoxia, oxidative stress drives oxidation of sGC heme (Fe²⁺→Fe³⁺), rendering it NO-insensitive. We previously showed that cytochrome b5 reductase 3 (CYB5R3) in SMC is a sGC reductase important for maintaining NO-dependent vasodilation and conferring resilience to systemic hypertension2022-01-01T00:00:00Z2022 Jan2025-04-21T15:23:08.987Z2025-04-21T15:23:08.987ZS-EPMC87669053453643910.1016/j.yjmcc.2021.09.005