{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T13:28:55Z","timestamp":1789824535897,"version":"4.0.1"},"reference-count":39,"publisher":"SAGE Publications","issue":"5","license":[{"start":{"date-parts":[[2011,12,21]],"date-time":"2011-12-21T00:00:00Z","timestamp":1324425600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Cereb Blood Flow Metab"],"published-print":{"date-parts":[[2012,5]]},"abstract":"<jats:p>\n                    Hyperhomocysteinemia (HHcy) disrupts nitric oxide (NO) signaling and increases nitrative stress in cerebral microvascular endothelial cells (CMVECs). This is mediated, in part, by protein nitrotyrosinylation (3-nitrotyrosine; 3-NT) though the mechanisms by which extracellular homocysteine (Hcy) generates intracellular 3-NT are unknown. Using a murine model of mild HHcy ( cbs\n                    <jats:sup>+\/\u2013<\/jats:sup>\n                    mouse), we show that 3-NT is significantly elevated in cerebral microvessels with concomitant reductions in serum NO bioavailability as compared with wild-type littermate controls ( cbs\n                    <jats:sup>+\/+<\/jats:sup>\n                    ). Directed pharmacology identified a receptor-dependent mechanism for 3-NT formation in CMVECs. Homocysteine increased expression of inducible NO synthase (iNOS) and formation of 3-NT, both of which were blocked by inhibition of metabotropic glutamate receptor-5 (mGluR5) with the specific antagonist 2-methyl-6-(phenylethynyl) pyridine hydrochloride. Activation of mGluR5 is both sufficient and necessary to drive the nitrative stress because direct activation using the mGluR5-specific agonist (RS)-2-chloro-5-hydroxyphenylglycine also increased iNOS expression and 3-NT formation while knockdown of mGluR5 receptor expression by short hairpin RNA (shRNA) blocked their increase in response to Hcy. Nitric oxide derived from iNOS was required for Hcy-mediated formation of 3-NT because the effect was blocked by 1400 W. These results provide the first evidence for a receptor-dependent process that explains how plasma Hcy levels control intracellular nitrative stress in cerebral microvascular endothelium.\n                  <\/jats:p>","DOI":"10.1038\/jcbfm.2011.185","type":"journal-article","created":{"date-parts":[[2011,12,21]],"date-time":"2011-12-21T06:00:46Z","timestamp":1324447246000},"page":"825-834","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":23,"title":["Nitrative Stress in Cerebral Endothelium is Mediated by mGluR5 in Hyperhomocysteinemia"],"prefix":"10.1177","volume":"32","author":[{"given":"Jamie N","family":"Mayo","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Idaho State University, Pocatello, Idaho, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Richard S","family":"Beard","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Idaho State University, Pocatello, Idaho, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tulin O","family":"Price","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Internal Medicine, Edward A. Doisy Research Center, Saint Louis University, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Hung","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Idaho State University, Pocatello, Idaho, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle A","family":"Erickson","sequence":"additional","affiliation":[{"name":"Geriatric Research Educational and Clinical Center (GRECC), Veterans Administration Puget Sound Health Care System, Seattle, Washington, USA"},{"name":"Division of Gerontology and Geriatric Medicine, Department of Internal Medicine, University of Washington School of Medicine, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuran","family":"Ercal","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Missouri University of Science and Technology, Rolla, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William A","family":"Banks","sequence":"additional","affiliation":[{"name":"Geriatric Research Educational and Clinical Center (GRECC), Veterans Administration Puget Sound Health Care System, Seattle, Washington, USA"},{"name":"Division of Gerontology and Geriatric Medicine, Department of Internal Medicine, University of Washington School of Medicine, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn E","family":"Bearden","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Idaho State University, Pocatello, Idaho, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2011,12,21]]},"reference":[{"key":"bibr1-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00598.2010"},{"key":"bibr2-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-02-338269"},{"key":"bibr3-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00555.2010"},{"key":"bibr4-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2007-11209"},{"key":"bibr5-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(01)00340-2"},{"key":"bibr6-jcbfm.2011.185","volume-title":"Homocysteine in Health and Disease","author":"Carmel R","year":"2001"},{"key":"bibr7-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000131749.81508.18"},{"key":"bibr8-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2002.tb02084.x"},{"key":"bibr9-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.31.5.1069"},{"key":"bibr10-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01310.2010"},{"key":"bibr11-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-5728(98)00201-X"},{"key":"bibr12-jcbfm.2011.185","first-page":"H2035","volume":"274","author":"Galea E","year":"1998","journal-title":"Am J Physiol"},{"key":"bibr13-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1016\/0361-9230(88)90047-0"},{"key":"bibr14-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.3109\/10715762.2010.512040"},{"key":"bibr15-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awh023"},{"key":"bibr16-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-06-2506"},{"key":"bibr17-jcbfm.2011.185","first-page":"103","volume":"5","author":"Khedr EM","year":"2009","journal-title":"Neuropsychiatr Dis Treat"},{"key":"bibr18-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2009.02.010"},{"key":"bibr19-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.9.1282"},{"key":"bibr20-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1159\/000071002"},{"key":"bibr21-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.2174\/1566524043479194"},{"key":"bibr22-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00833.2007"},{"key":"bibr23-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2007-11208"},{"key":"bibr24-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(01)02299-6"},{"key":"bibr25-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90009-4"},{"key":"bibr26-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00359.2005"},{"key":"bibr27-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(99)99025-0"},{"key":"bibr28-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2008.08.005"},{"key":"bibr29-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.65.5.642"},{"key":"bibr30-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.047092"},{"key":"bibr31-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000245082.19294.ff"},{"key":"bibr32-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64166-1"},{"key":"bibr33-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000061735.85377.40"},{"key":"bibr34-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.231428998"},{"key":"bibr35-jcbfm.2011.185","first-page":"22","volume":"110","author":"Welch GN","year":"1998","journal-title":"Proc Assoc Am Physicians"},{"key":"bibr36-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1006\/abio.1995.1246"},{"key":"bibr37-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.13.6954"},{"key":"bibr38-jcbfm.2011.185","doi-asserted-by":"publisher","DOI":"10.1358\/mf.2005.27.10.948913"},{"key":"bibr39-jcbfm.2011.185","doi-asserted-by":"crossref","first-page":"301","DOI":"10.55782\/ane-2006-1619","volume":"66","author":"Zieminska E","year":"2006","journal-title":"Acta Neurobiol Exp (Wars)"}],"container-title":["Journal of Cerebral Blood Flow &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1038\/jcbfm.2011.185","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1038\/jcbfm.2011.185","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1038\/jcbfm.2011.185","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T20:10:11Z","timestamp":1777493411000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1038\/jcbfm.2011.185"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,12,21]]},"references-count":39,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2012,5]]}},"alternative-id":["10.1038\/jcbfm.2011.185"],"URL":"https:\/\/doi.org\/10.1038\/jcbfm.2011.185","relation":{},"ISSN":["0271-678X","1559-7016"],"issn-type":[{"value":"0271-678X","type":"print"},{"value":"1559-7016","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,12,21]]}}}