{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:30:19Z","timestamp":1791354619898,"version":"4.3.1"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2008,2,26]]},"abstract":"<jats:p>\n                    <jats:bold>\n                      <jats:italic>Background\u2014<\/jats:italic>\n                    <\/jats:bold>\n                    Tetrahydrobiopterin (BH4) is an essential cofactor of endothelial nitric oxide synthase (eNOS). When BH4 levels are decreased, eNOS becomes uncoupled to produce superoxide anion (O\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    ) instead of NO, which contributes to endothelial dysfunction. Deoxycorticosterone acetate (DOCA)\u2013salt hypertension is characterized by a suppressed plasma renin level due to sodium retention but manifests in eNOS uncoupling; however, how endogenous BH4 regulates blood pressure is unknown. GTP cyclohydrolase I (GTPCH I) is the rate-limiting enzyme for de novo BH4 synthesis. This study tested the hypothesis that endothelium-specific GTPCH I overexpression retards the progression of hypertension through preservation of the structure and function of resistance mesenteric arteries.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>\n                      <jats:italic>Methods and Results\u2014<\/jats:italic>\n                    <\/jats:bold>\n                    During 3 weeks of DOCA-salt treatment, arterial blood pressure was increased significantly in wild-type mice, as determined by radiotelemetry, but this increase was attenuated in transgenic mice with endothelium-specific GTPCH I overexpression (Tg-GCH). Arterial GTPCH I activity and BH4 levels were decreased significantly in wild-type DOCA-salt mice, but both were preserved in Tg-GCH mice despite DOCA-salt treatment. Significant remodeling of resistance mesenteric arteries (\u2248100-\u03bcm outside diameter) in wild-type DOCA-salt mice exists, evidenced by increased medial cross-sectional area, media thickness, and media-lumen ratio and overexpression of tenascin C, an extracellular matrix glycoprotein that contributes to hypertrophic remodeling; all of these effects were prevented in DOCA-salt\u2013treated Tg-GCH mice. Furthermore, NO-mediated relaxation in mesenteric arteries was significantly improved in DOCA-salt\u2013treated Tg-GCH mice, in parallel with reduced O\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    levels. Finally, phosphorylation of eNOS at serine residue 1177 (eNOS-S\n                    <jats:sup>1177<\/jats:sup>\n                    ), but not its dimer-monomer ratio, was decreased significantly in wild-type DOCA-salt mice compared with sham controls but was preserved in DOCA-salt\u2013treated Tg-GCH mice.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>\n                      <jats:italic>Conclusions\u2014<\/jats:italic>\n                    <\/jats:bold>\n                    These results demonstrate that endothelium-specific GTPCH I overexpression abrogates O\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    production and preserves eNOS phosphorylation, which results in preserved structural and functional integrity of resistance mesenteric arteries and lowered blood pressure in low-renin hypertension.\n                  <\/jats:p>","DOI":"10.1161\/circulationaha.107.748236","type":"journal-article","created":{"date-parts":[[2008,2,11]],"date-time":"2008-02-11T21:10:13Z","timestamp":1202764213000},"page":"1045-1054","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":96,"title":["Endothelium-Specific GTP Cyclohydrolase I Overexpression Attenuates Blood Pressure Progression in Salt-Sensitive Low-Renin Hypertension"],"prefix":"10.1161","volume":"117","author":[{"given":"Yan-Hua","family":"Du","sequence":"first","affiliation":[{"name":"From the Departments of Pharmacology and Neurology (Y.-H.D., A.F.C.), Neuroscience Program and Cell and Molecular Biology Program, Michigan State University, East Lansing; Department of Pharmacology (Y.-H.D., Y.-Y.G.), Sun Yat-Sen University, Guangzhou, China; and Department of Cardiovascular Medicine (N.J.A., K.M.C.), John Radcliffe Hospital, Oxford University, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Yuan","family":"Guan","sequence":"additional","affiliation":[{"name":"From the Departments of Pharmacology and Neurology (Y.-H.D., A.F.C.), Neuroscience Program and Cell and Molecular Biology Program, Michigan State University, East Lansing; Department of Pharmacology (Y.-H.D., Y.-Y.G.), Sun Yat-Sen University, Guangzhou, China; and Department of Cardiovascular Medicine (N.J.A., K.M.C.), John Radcliffe Hospital, Oxford University, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Alp","sequence":"additional","affiliation":[{"name":"From the Departments of Pharmacology and Neurology (Y.-H.D., A.F.C.), Neuroscience Program and Cell and Molecular Biology Program, Michigan State University, East Lansing; Department of Pharmacology (Y.-H.D., Y.-Y.G.), Sun Yat-Sen University, Guangzhou, China; and Department of Cardiovascular Medicine (N.J.A., K.M.C.), John Radcliffe Hospital, Oxford University, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith M.","family":"Channon","sequence":"additional","affiliation":[{"name":"From the Departments of Pharmacology and Neurology (Y.-H.D., A.F.C.), Neuroscience Program and Cell and Molecular Biology Program, Michigan State University, East Lansing; Department of Pharmacology (Y.-H.D., Y.-Y.G.), Sun Yat-Sen University, Guangzhou, China; and Department of Cardiovascular Medicine (N.J.A., K.M.C.), John Radcliffe Hospital, Oxford University, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex F.","family":"Chen","sequence":"additional","affiliation":[{"name":"From the Departments of Pharmacology and Neurology (Y.-H.D., A.F.C.), Neuroscience Program and Cell and Molecular Biology Program, Michigan State University, East Lansing; Department of Pharmacology (Y.-H.D., Y.-Y.G.), Sun Yat-Sen University, Guangzhou, China; and Department of Cardiovascular Medicine (N.J.A., K.M.C.), John Radcliffe Hospital, Oxford University, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.atv.0000149143.04821.eb"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00253.2003"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000089082.40285.c3"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200314172"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.2007.04719.x"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI17786"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-005-1857-5"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.atv.0000115637.48689.77"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(99)80371-6"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2005.02.014"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00272-9"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000051459.74466.46"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2005.07.007"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0705255"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0705549"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(03)00424-3"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.1998.0841"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0895-7061(01)02233-6"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.atv.0000047447.67827.cd"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000146279.11923.14"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.79.6.1131"},{"key":"e_1_3_2_22_2","first-page":"377","volume":"141","year":"1992","unstructured":"Mackie EJ, Scott-Burden T, Hahn AW, Kern F, Bernhardt J, Regenass S, Weller A, Buhler FR. 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