{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:58:53Z","timestamp":1790283533061,"version":"4.1.0"},"reference-count":45,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2017,3,13]],"date-time":"2017-03-13T00:00:00Z","timestamp":1489363200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005617","name":"BHF Centre of Research Excellence, Oxford","doi-asserted-by":"publisher","award":["RE\/13\/1\/30181"],"award-info":[{"award-number":["RE\/13\/1\/30181"]}],"id":[{"id":"10.13039\/501100005617","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["RG\/12\/5\/29576"],"award-info":[{"award-number":["RG\/12\/5\/29576"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2017,4]]},"abstract":"\n Background and Purpose<\/jats:title>\n \n The cofactor tetrahydrobiopterin (BH4) is a critical regulator of endothelial NOS (eNOS) function, eNOS\u2010derived NO and ROS signalling in vascular physiology. To determine the physiological requirement for\n de novo<\/jats:italic>\n endothelial cell BH4 synthesis for the vasomotor function of resistance arteries, we have generated a mouse model with endothelial cell\u2010specific deletion of\n Gch1,<\/jats:italic>\n encoding GTP cyclohydrolase 1 (GTPCH), an essential enzyme for BH4 biosynthesis, and evaluated BH4\u2010dependent eNOS regulation, eNOS\u2010derived NO and ROS generation.\n <\/jats:p>\n <\/jats:sec>\n \n Experimental Approach<\/jats:title>\n The reactivity of mouse second\u2010order mesenteric arteries was assessed by wire myography. High performance liquid chromatography was used to determine BH4, BH2 and biopterin. Western blotting was used for expression analysis.<\/jats:p>\n <\/jats:sec>\n \n Key Results<\/jats:title>\n \n Gch1<\/jats:italic>\n \n fl\/fl<\/jats:italic>\n <\/jats:sup>\n Tie2cre mice demonstrated reduced GTPCH protein and BH4 levels in mesenteric arteries. Deficiency in endothelial cell BH4 leads to eNOS uncoupling, increased ROS production and loss of NO generation in mesenteric arteries of\n Gch1<\/jats:italic>\n \n fl\/fl<\/jats:italic>\n <\/jats:sup>\n Tie2cre mice.\n Gch1<\/jats:italic>\n \n fl\/fl<\/jats:italic>\n <\/jats:sup>\n Tie2cre mesenteric arteries had enhanced vasoconstriction to U46619 and phenylephrine, which was abolished by L\u2010NAME. Endothelium\u2010dependent vasodilatations to ACh and SLIGRL were impaired in mesenteric arteries from\n Gch1<\/jats:italic>\n \n fl\/fl<\/jats:italic>\n <\/jats:sup>\n Tie2cre mice, compared with those from wild\u2010type littermates. Loss of eNOS\u2010derived NO\u2010mediated vasodilatation was associated with increased eNOS\u2010derived H\n 2<\/jats:sub>\n O\n 2<\/jats:sub>\n and cyclooxygenase\u2010derived vasodilator in\n Gch1<\/jats:italic>\n \n fl\/fl<\/jats:italic>\n <\/jats:sup>\n Tie2cre mesenteric arteries.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Implications<\/jats:title>\n \n Endothelial cell\n Gch1<\/jats:italic>\n and BH4\u2010dependent eNOS regulation play pivotal roles in maintaining vascular homeostasis in resistance arteries. Therefore, targeting vascular\n Gch1<\/jats:italic>\n and BH4 biosynthesis may provide a novel therapeutic target for the prevention and treatment of microvascular dysfunction in patients with cardiovascular disease.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/bph.13728","type":"journal-article","created":{"date-parts":[[2017,1,27]],"date-time":"2017-01-27T05:58:48Z","timestamp":1485496728000},"page":"657-671","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["A key role for tetrahydrobiopterin\u2010dependent endothelial NOS regulation in resistance arteries: studies in endothelial cell tetrahydrobiopterin\u2010deficient mice"],"prefix":"10.1111","volume":"174","author":[{"given":"Surawee","family":"Chuaiphichai","sequence":"first","affiliation":[{"name":"British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine University of Oxford Oxford UK"},{"name":"Wellcome Trust Centre for 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