{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T09:38:37Z","timestamp":1790242717876,"version":"4.1.0"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2002,3,19]]},"abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>\n                <jats:bold>\n                  <jats:italic>Background<\/jats:italic>\n                <\/jats:bold>\n                \u2014\n              <\/jats:italic>\n            <\/jats:bold>\n            Nontranscriptional signaling through estrogen receptors (ERs) is important in the cardiovascular system. In particular, estrogen stimulates endothelial NO synthase (eNOS) via the phosphatidylinositol 3-kinase (PI3K) pathway. The selective estrogen receptor modulator (SERM) raloxifene is effective for the treatment of postmenopausal osteoporosis, but its ability to activate eNOS via PI3K is unknown.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>\n                <jats:bold>\n                  <jats:italic>Methods and Results<\/jats:italic>\n                <\/jats:bold>\n                \u2014\n              <\/jats:italic>\n            <\/jats:bold>\n            Human umbilical vein endothelial cells were cultured in estrogen-deprived, phenol red-free medium. Raloxifene stimulated eNOS in a concentration- and time-dependent manner. Activation of eNOS by raloxifene was blocked by the PI3K inhibitor wortmannin and by the ER antagonist ICI 182,780 but not by transcriptional or translational inhibitors. Coimmunoprecipitation studies demonstrated that, in a ligand-dependent manner, raloxifene increased ER\u03b1-associated p85\u03b1, p110\u03b1, and PI3K activity. This correlated temporally with increases in the serine and threonine phosphorylation and activation of protein kinase Akt.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>\n                <jats:bold>\n                  <jats:italic>Conclusions<\/jats:italic>\n                <\/jats:bold>\n                \u2014\n              <\/jats:italic>\n            <\/jats:bold>\n            Our findings indicate that nongenomic ER signaling triggered by a SERM leads to a rapid activation of NO synthesis in human endothelial cells. The ability of raloxifene to facilitate ER\u03b1-PI3K interaction may provide additional insight into the structure-function relationship of specific SERMs, which promote the nontranscriptional effects of ER.\n          <\/jats:p>","DOI":"10.1161\/hc1102.105267","type":"journal-article","created":{"date-parts":[[2002,7,28]],"date-time":"2002-07-28T23:16:07Z","timestamp":1027898167000},"page":"1368-1373","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":88,"title":["Nongenomic Mechanisms of Endothelial Nitric Oxide Synthase Activation by the Selective Estrogen Receptor Modulator Raloxifene"],"prefix":"10.1161","volume":"105","author":[{"given":"Tommaso","family":"Simoncini","sequence":"first","affiliation":[{"name":"From the Department of Reproductive Medicine and Child Development (T.S., A.R.G.), Division of Obstetrics and Gynecology, University of Pisa, Italy, and Cardiovascular Division (J.K.L.), Department of Medicine, Brigham &amp; Women\u2019s Hospital and Harvard Medical School, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea R.","family":"Genazzani","sequence":"additional","affiliation":[{"name":"From the Department of Reproductive Medicine and Child Development (T.S., A.R.G.), Division of Obstetrics and Gynecology, University of Pisa, Italy, and Cardiovascular Division (J.K.L.), Department of Medicine, Brigham &amp; Women\u2019s Hospital and Harvard Medical School, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James K.","family":"Liao","sequence":"additional","affiliation":[{"name":"From the Department of Reproductive Medicine and Child Development (T.S., A.R.G.), Division of Obstetrics and Gynecology, University of Pisa, Italy, and Cardiovascular Division (J.K.L.), Department of Medicine, Brigham &amp; Women\u2019s Hospital and Harvard Medical School, Boston, Mass."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199711063371906"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1080\/13697130008500127"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.104.4.499"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-5122(98)00109-1"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199712043372301"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.279.18.1445"},{"key":"e_1_3_2_7_2","first-page":"214","volume":"85","year":"2000","unstructured":"Walsh BW, Paul S, Wild RA, et al. The effects of hormone replacement therapy and raloxifene on C-reactive protein and homocysteine in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab. 2000; 85: 214\u2013218.","journal-title":"J Clin Endocrinol Metab"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199906103402306"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1097\/00001703-200006000-00004"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.96.6.1964"},{"key":"e_1_3_2_11_2","first-page":"721","volume":"83","year":"1998","unstructured":"Clarkson TB, Anthony MS, Jerome CP. Lack of effect of raloxifene on coronary artery atherosclerosis of postmenopausal monkeys. 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Endothelial nitric oxide and vascular inflammation. In: Panza JA Cannon ROI eds. Endothelium Nitric Oxide and Atherosclerosis. Armonk NY: Futura Publishing Co; 1999: 119\u2013132."},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.84.2.5570"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118074"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.280.7.605"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200008243430801"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.13.8347"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/hc1102.105267","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T01:38:44Z","timestamp":1715650724000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/hc1102.105267"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,3,19]]},"references-count":32,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2002,3,19]]}},"alternative-id":["10.1161\/hc1102.105267"],"URL":"https:\/\/doi.org\/10.1161\/hc1102.105267","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2002,3,19]]},"assertion":[{"value":"2002-02-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}