{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T16:59:43Z","timestamp":1773766783918,"version":"3.50.1"},"reference-count":47,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2005,12,9]],"date-time":"2005-12-09T00:00:00Z","timestamp":1134086400000},"content-version":"vor","delay-in-days":5943,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[1989,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Neovascularization in the rheumatoid synovium plays an important role in the propagation of rheumatoid synovitis because the emigration of mononuclear cells and the growth of pannus are critically dependent on the development of small blood vessels. Inhibition of local vascular endothelial cell (EC) proliferation, which is essential for growth of these vessels, therefore, would have the potential to suppress rheumatoid inflammation. We investigated the effects of methotrexate (MTX), low doses of which are commonly administered to rheumatoid arthritis patients, on DNA synthesis by human umbilical vein EC in vitro and on rabbit corneal neovascularization in vivo. MTX inhibited both basal and EC growth factor\u2013stimulated tritiated deoxyuridine (<jats:sup>3<\/jats:sup>H\u2010UdR) incorporation into EC in a dose\u2010dependent manner. Significant inhibition was observed at a concentration of 5 \u00d7 10<jats:sup>\u22129<\/jats:sup><jats:italic>M<\/jats:italic>, which is that attained in the serum of treated patients. Neovascularization in vivo was also suppressed by low\u2010dose intramuscular injections. These results suggest that MTX has an antiangiogenic effect, and may suppress rheumatoid inflammation through the reduction of synovial small blood vessels responsible for mononuclear cell infiltration and proliferation of synovial tissue.<\/jats:p>","DOI":"10.1002\/anr.1780320903","type":"journal-article","created":{"date-parts":[[2007,2,14]],"date-time":"2007-02-14T23:10:29Z","timestamp":1171494629000},"page":"1065-1073","source":"Crossref","is-referenced-by-count":160,"title":["Inhibition of in vitro vascular endothelial cell proliferation and in vivo neovascularization by low\u2010dose methotrexate"],"prefix":"10.1002","volume":"32","author":[{"given":"S.","family":"Hirata","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T.","family":"Matsubara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R.","family":"Saura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K.","family":"Hirohata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H.","family":"Tateishi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2005,12,14]]},"reference":[{"key":"e_1_2_1_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2776(08)60299-0"},{"key":"e_1_2_1_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-230X(08)60946-X"},{"key":"e_1_2_1_4_2","first-page":"249s","article-title":"Antigen\u2010presenting properties of human vascular endothelial cells","volume":"152","author":"Hirshberg H","year":"1980","journal-title":"J Exp Med"},{"key":"e_1_2_1_5_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI110179"},{"key":"e_1_2_1_6_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.157.4.1339"},{"key":"e_1_2_1_7_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.162.4.1223"},{"key":"e_1_2_1_8_2","doi-asserted-by":"crossref","first-page":"2486","DOI":"10.4049\/jimmunol.136.7.2486","article-title":"Production of interleukin 1 by human endothelial cells","volume":"136","author":"Miossec P","year":"1986","journal-title":"J Immunol"},{"key":"e_1_2_1_9_2","first-page":"501","article-title":"Low dose pulse methotrexate therapy in rheumatoid arthritis","volume":"7","author":"Willkens RF","year":"1980","journal-title":"J Rheumatol"},{"key":"e_1_2_1_10_2","first-page":"860","article-title":"Low dose methotrexate in rheumatoid arthritis","volume":"9","author":"Steinsson K","year":"1982","journal-title":"J Rheumatol"},{"key":"e_1_2_1_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(83)90477-1"},{"key":"e_1_2_1_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(85)90312-2"},{"key":"e_1_2_1_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780290702"},{"key":"e_1_2_1_14_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI107417"},{"key":"e_1_2_1_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI108241"},{"key":"e_1_2_1_16_2","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-70-3-535"},{"key":"e_1_2_1_17_2","first-page":"346","article-title":"Comparative study of cyclophosphamide, 6\u2010mercaptopurine, azathiopurine and methotrexate: relative effects of the humoral and cellular immune response in the mouse","volume":"26","author":"Otternes IG","year":"1976","journal-title":"Clin Exp Immunol"},{"key":"e_1_2_1_18_2","first-page":"1716","article-title":"Differential lethal effects of cytotoxic agents on proliferating and nonproliferating lymphoid cells","volume":"33","author":"Lin H","year":"1973","journal-title":"Cancer Res"},{"key":"e_1_2_1_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/52.2.413"},{"key":"e_1_2_1_20_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI107470"},{"key":"e_1_2_1_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.1982.tb00753.x"},{"key":"e_1_2_1_22_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.99.6.2034"},{"key":"e_1_2_1_23_2","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1055\/s-0038-1642767","article-title":"Cytomegalovirus alters the von Willebrand factor content in human endothelial cells","volume":"59","author":"Bruggeman CA","year":"1988","journal-title":"Thromb Haemost"},{"key":"e_1_2_1_24_2","first-page":"1286","article-title":"The mechanism of action of the folate antagonists in man","volume":"23","author":"Bertino JR","year":"1963","journal-title":"Cancer Res"},{"key":"e_1_2_1_25_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI106181"},{"key":"e_1_2_1_26_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI107362"},{"key":"e_1_2_1_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.73.3.945"},{"key":"e_1_2_1_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/263797a0"},{"key":"e_1_2_1_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1984.47"},{"key":"e_1_2_1_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780290703"},{"key":"e_1_2_1_31_2","first-page":"3531","article-title":"Evaluation of ribonucleoside and deoxyribonucleoside triphosphate pools in cultured leukemia cells during exposure to methotrexate or methotrexate plus thymidine","volume":"39","author":"Kinahan JJ","year":"1979","journal-title":"Cancer Res"},{"key":"e_1_2_1_32_2","first-page":"281","article-title":"Modulation of methotrexate toxicity by thymidine: sequence\u2010dependent biochemical effects","volume":"18","author":"Jackson RC","year":"1980","journal-title":"Mol Pharmacol"},{"key":"e_1_2_1_33_2","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12466229"},{"key":"e_1_2_1_34_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112475"},{"key":"e_1_2_1_35_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.139.6.1855"},{"key":"e_1_2_1_36_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.05.040187.001221"},{"key":"e_1_2_1_37_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112312"},{"key":"e_1_2_1_38_2","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.4049\/jimmunol.138.6.1762","article-title":"Human monocyte adhesion: a primary effect of chemotactic factors on the monocyte to stimulate adherence to human endothelium","volume":"138","author":"Doherty DE","year":"1987","journal-title":"J Immunol"},{"key":"e_1_2_1_39_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112200"},{"key":"e_1_2_1_40_2","first-page":"4441","article-title":"Differential synthesis of methotrexate polyglutamates in normal proliferative and neoplastic mouse tissues in vivo","volume":"41","author":"Poser RG","year":"1981","journal-title":"Cancer Res"},{"key":"e_1_2_1_41_2","first-page":"3190","article-title":"Polyglutamation, an important element in methotrexate cytotoxicity and selectivity in tumor versus murine granulocytic progenitor cells in vitro","volume":"44","author":"Fabre I","year":"1984","journal-title":"Cancer Res"},{"key":"e_1_2_1_42_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198311033091805"},{"key":"e_1_2_1_43_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112088"},{"key":"e_1_2_1_44_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI111661"},{"key":"e_1_2_1_45_2","first-page":"2547","article-title":"Chemotaxis of aortic endothelial cells in response to fibronectin","volume":"42","author":"Bowersox JC","year":"1982","journal-title":"Cancer Res"},{"key":"e_1_2_1_46_2","doi-asserted-by":"crossref","first-page":"3295","DOI":"10.4049\/jimmunol.137.10.3295","article-title":"Increased superoxide anion release from human endothelial cells in response to cyto\u2010kines","volume":"137","author":"Matsubara T","year":"1986","journal-title":"J Immunol"},{"key":"e_1_2_1_47_2","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.4049\/jimmunol.126.4.1510","article-title":"Stimulation of nonlymphoid mesenchymal cell proliferation by a macrophage\u2010derived growth factor","volume":"126","author":"Martin BM","year":"1981","journal-title":"J Immunol"},{"key":"e_1_2_1_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/269804a0"}],"container-title":["Arthritis &amp; Rheumatism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fanr.1780320903","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anr.1780320903","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T07:17:14Z","timestamp":1700723834000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anr.1780320903"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1989,9]]},"references-count":47,"journal-issue":{"issue":"9","published-print":{"date-parts":[[1989,9]]}},"alternative-id":["10.1002\/anr.1780320903"],"URL":"https:\/\/doi.org\/10.1002\/anr.1780320903","archive":["Portico"],"relation":{},"ISSN":["0004-3591","1529-0131"],"issn-type":[{"value":"0004-3591","type":"print"},{"value":"1529-0131","type":"electronic"}],"subject":[],"published":{"date-parts":[[1989,9]]}}}