{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T03:14:29Z","timestamp":1790306069471,"version":"4.1.0"},"reference-count":55,"publisher":"American Society for Clinical Investigation","issue":"19","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 HL 133864"],"award-info":[{"award-number":["R01 HL 133864"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 HL 128304"],"award-info":[{"award-number":["R01 HL 128304"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["16GRNT27250146"],"award-info":[{"award-number":["16GRNT27250146"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["T32 DK007052"],"award-info":[{"award-number":["T32 DK007052"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Bayer AG Sponsored Research Funds","award":["1"],"award-info":[{"award-number":["1"]}]},{"name":"Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania","award":["1"],"award-info":[{"award-number":["1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,3]]},"abstract":"<jats:p>\n                    Nitric oxide regulates BP by binding the reduced heme iron (Fe\n                    <jats:sup>2+<\/jats:sup>\n                    ) in soluble guanylyl cyclase (sGC) and relaxing vascular smooth muscle cells (SMCs). We previously showed that sGC heme iron reduction (Fe\n                    <jats:sup>3+<\/jats:sup>\n                    \u2192 Fe\n                    <jats:sup>2+<\/jats:sup>\n                    ) is modulated by cytochrome b5 reductase 3 (CYB5R3). However, the in vivo role of SMC CYB5R3 in BP regulation remains elusive. Here, we generated conditional smooth muscle cell\u2013specific\n                    <jats:italic>Cyb5r3<\/jats:italic>\n                    KO mice (SMC CYB5R3\u2013KO) to test if SMC CYB5R3 loss affects systemic BP in normotension and hypertension via regulation of the sGC redox state. SMC CYB5R3\u2013KO mice exhibited a 5.84-mmHg increase in BP and impaired acetylcholine-induced vasodilation in mesenteric arteries compared with controls. To drive sGC oxidation and elevate BP, we infused mice with angiotensin II. We found that SMC CYB5R3\u2013KO mice exhibited a 14.75-mmHg BP increase, and mesenteric arteries had diminished nitric oxide\u2013dependent vasodilation but increased responsiveness to sGC heme-independent activator BAY 58-2667 over controls. Furthermore, acute injection of BAY 58-2667 in angiotensin II\u2013treated SMC CYB5R3\u2013KO mice showed greater BP reduction compared with controls. Together, these data provide the first in vivo evidence to our knowledge that SMC CYB5R3 is an sGC heme reductase in resistance arteries and provides resilience against systemic hypertension development.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.129183","type":"journal-article","created":{"date-parts":[[2019,9,5]],"date-time":"2019-09-05T12:01:05Z","timestamp":1567684865000},"source":"Crossref","is-referenced-by-count":51,"title":["Loss of smooth muscle CYB5R3 amplifies angiotensin II\u2013induced hypertension by increasing sGC heme oxidation"],"prefix":"10.1172","volume":"4","author":[{"given":"Brittany G.","family":"Durgin","sequence":"first","affiliation":[{"name":"Heart, Lung, Blood and Vascular Medicine Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A.","family":"Hahn","sequence":"additional","affiliation":[{"name":"Heart, Lung, Blood and Vascular Medicine Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3084-9094","authenticated-orcid":true,"given":"Heidi M.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Heart, Lung, Blood and Vascular Medicine Institute, and"},{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan P.","family":"Miller","sequence":"additional","affiliation":[{"name":"Heart, Lung, Blood and Vascular Medicine Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Hafeez","sequence":"additional","affiliation":[{"name":"Heart, Lung, Blood and Vascular Medicine Institute, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilka","family":"Mathar","sequence":"additional","affiliation":[{"name":"Bayer AG, Wuppertal, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0857-8950","authenticated-orcid":true,"given":"Daniel","family":"Freitag","sequence":"additional","affiliation":[{"name":"Bayer AG, Wuppertal, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Sandner","sequence":"additional","affiliation":[{"name":"Bayer AG, Wuppertal, Germany."},{"name":"Department of Pharmacology, Hannover Medical School, Hannover, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam C.","family":"Straub","sequence":"additional","affiliation":[{"name":"Heart, Lung, Blood and Vascular Medicine Institute, and"},{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2019,10,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.190333697"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1021\/bi971825x"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1021\/bi051601b"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2009.02.009"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.niox.2018.03.013"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1301934110"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M706218200"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.42.24871"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1124\/mol.107.036368"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28371"},{"issue":"1","key":"B11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0026-895X(25)09113-8","article-title":"Characterization of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one as a heme-site inhibitor of nitric oxide-sensitive guanylyl cyclase","volume":"50","author":"Schrammel","year":"1996","journal-title":"Mol Pharmacol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0704778"},{"issue":"6","key":"B13","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1038\/sj.bjp.0706792","article-title":"NO-independent activation of soluble guanylate cyclase prevents disease progression in rats with 5\/6 nephrectomy","volume":"148","author":"Kalk","year":"2006","journal-title":"Br J Pharmacol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/newbio229252a0"},{"issue":"1","key":"B15","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/0005-2728(72)90024-2","article-title":"Soluble cytochrome b5 reductase from human erythrocytes","volume":"275","author":"Passon","year":"1972","journal-title":"Biochim Biophys Acta"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a129444"},{"key":"B17","doi-asserted-by":"crossref","DOI":"10.1038\/npjamd.2016.6","article-title":"Cytochrome b5 reductase and the control of lipid metabolism and healthspan","volume":"2","author":"Martin-Montalvo","year":"2016","journal-title":"NPJ Aging Mech Dis"},{"issue":"9","key":"B18","doi-asserted-by":"crossref","first-page":"2797","DOI":"10.1016\/S0021-9258(17)40432-7","article-title":"Mechanism of C-5 double bond introduction in the biosynthesis of cholesterol by rat liver microsomes","volume":"252","author":"Reddy","year":"1977","journal-title":"J Biol Chem"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(71)90186-X"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e3283343296"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2013.5479"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.303974"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nature11626"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.310705"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/nm1666"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/s11906-010-0118-2"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.303776"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s11906-012-0320-5"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.629964"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00315.2016"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1042\/CS20090096"},{"issue":"5\u20136","key":"B32","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s10863-006-9050-1","article-title":"Adaptations to oxidative stress induced by vitamin E deficiency in rat liver","volume":"38","author":"de Cabo","year":"2006","journal-title":"J Bioenerg Biomembr"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1124\/mol.112.084616"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2013.04.028"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.7b00224"},{"key":"B36","article-title":"Cytoglobin regulates blood pressure and vascular tone through nitric oxide metabolism in the vascular wall","volume":"8","author":"Liu","year":"2017","journal-title":"Nat Commun"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2012.4604"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2009.07.023"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.108.181925"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3403"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2005.12.049"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.107.089706"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.538934"},{"issue":"1 pt 2","key":"B44","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1161\/01.HYP.29.1.366","article-title":"Angiotensin II signaling in vascular smooth muscle. New concepts","volume":"29","author":"Griendling","year":"1997","journal-title":"Hypertension"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.108.181610"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2013.03.019"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.259242"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/ncb775"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12767"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jbchem.a129444"},{"issue":"9","key":"B51","doi-asserted-by":"crossref","first-page":"2797","DOI":"10.1016\/S0021-9258(17)40432-7","article-title":"Mechanism of C-5 double bond introduction in the biosynthesis of cholesterol by rat liver microsomes","volume":"252","author":"Reddy","year":"1977","journal-title":"J Biol Chem"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/nature10163"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1521"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1342"},{"issue":"20","key":"B55","doi-asserted-by":"crossref","first-page":"14509","DOI":"10.1016\/S0021-9258(17)36652-8","article-title":"cAMP- and cGMP-dependent protein kinase phosphorylation sites of the focal adhesion vasodilator-stimulated phosphoprotein (VASP) in vitro and in intact human platelets","volume":"269","author":"Butt","year":"1994","journal-title":"J Biol Chem"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/129183\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:24:29Z","timestamp":1779193469000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/129183"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,3]]},"references-count":55,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2019,10,3]]},"published-print":{"date-parts":[[2019,10,3]]}},"alternative-id":["10.1172\/jci.insight.129183"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.129183","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,3]]},"article-number":"e129183"}}