{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T03:41:46Z","timestamp":1789962106542,"version":"4.0.1"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"19","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2007,11,6]]},"abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>Background\u2014<\/jats:italic>\n            <\/jats:bold>\n            Neurofibromatosis type I (NF1) is a common autosomal dominant disorder with a broad array of clinical manifestations, including benign and malignant tumors, osseous dysplasias, and characteristic cutaneous findings. In addition, NF1 patients have an increased incidence of cardiovascular diseases, including obstructive vascular disorders. In animal models, endothelial expression of the disease gene,\n            <jats:italic>NF1<\/jats:italic>\n            , is critical for normal heart development. However, the pathogeneses of the more common vascular disorders are not well characterized.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Methods and Results\u2014<\/jats:italic>\n            <\/jats:bold>\n            To examine the role of\n            <jats:italic>NF1<\/jats:italic>\n            in vascular smooth muscle, we generated mice with homozygous loss of the murine homolog\n            <jats:italic>Nf1<\/jats:italic>\n            in smooth muscle (\n            <jats:italic>Nf1<\/jats:italic>\n            smKO). These mice develop and breed normally. However, in response to vascular injury, they display a marked intimal hyperproliferation and abnormal activation of mitogen- activated protein kinase, a downstream effector of Ras. Vascular smooth muscle cells cultured from these mice also display enhanced proliferation and mitogen-activated protein kinase activity. Smooth muscle expression of the\n            <jats:italic>NF1<\/jats:italic>\n            Ras-regulatory domain (GTPase activating protein\u2013related domain) rescues intimal hyperplasia in\n            <jats:italic>Nf1<\/jats:italic>\n            smKO mice and normalizes vascular smooth muscle cell Ras effector activity and proliferation in vitro, similar to blockade of downstream effectors of Ras.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Conclusions\u2014<\/jats:italic>\n            <\/jats:bold>\n            In this in vivo model of NF1 obstructive vascular disease, we have shown that\n            <jats:italic>Nf1<\/jats:italic>\n            regulation of Ras plays a critical role in vascular smooth muscle proliferation after injury. These results suggest opportunities for targeted therapeutics in the prevention and treatment of NF1-related vascular disease and in the treatment of neointimal proliferation in other settings.\n          <\/jats:p>","DOI":"10.1161\/circulationaha.107.707752","type":"journal-article","created":{"date-parts":[[2007,10,22]],"date-time":"2007-10-22T23:10:53Z","timestamp":1193094653000},"page":"2148-2156","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":72,"title":["<i>NF1<\/i>\n            Regulates a Ras-Dependent Vascular Smooth Muscle Proliferative Injury Response"],"prefix":"10.1161","volume":"116","author":[{"given":"Junwang","family":"Xu","sequence":"first","affiliation":[{"name":"From the Department of Cell and Developmental Biology and Penn Cardiovascular Institute, University of Pennsylvania (J.X., F.A.I., T.W., J.Y., J.A.E.), and Division of Cardiology, Department of Pediatrics, Children\u2019s Hospital of Philadelphia (F.A.I.), Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fraz A.","family":"Ismat","sequence":"additional","affiliation":[{"name":"From the Department of Cell and Developmental Biology and Penn Cardiovascular Institute, University of Pennsylvania (J.X., F.A.I., T.W., J.Y., J.A.E.), and Division of Cardiology, Department of Pediatrics, Children\u2019s Hospital of Philadelphia (F.A.I.), Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Department of Cell and Developmental Biology and Penn Cardiovascular Institute, University of Pennsylvania (J.X., F.A.I., T.W., J.Y., J.A.E.), and Division of Cardiology, Department of Pediatrics, Children\u2019s Hospital of Philadelphia (F.A.I.), Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jifu","family":"Yang","sequence":"additional","affiliation":[{"name":"From the Department of Cell and Developmental Biology and Penn Cardiovascular Institute, University of Pennsylvania (J.X., F.A.I., T.W., J.Y., J.A.E.), and Division of Cardiology, Department of Pediatrics, Children\u2019s Hospital of Philadelphia (F.A.I.), Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A.","family":"Epstein","sequence":"additional","affiliation":[{"name":"From the Department of Cell and Developmental Biology and Penn Cardiovascular Institute, University of Pennsylvania (J.X., F.A.I., T.W., J.Y., J.A.E.), and Division of Cardiology, Department of Pediatrics, Children\u2019s Hospital of Philadelphia (F.A.I.), Philadelphia, Pa."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1097\/00019052-200404000-00004"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00245-8"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.125.22.4359"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/00125817-200205000-00002"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1136\/thx.52.6.577"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1136\/pgmj.74.877.679"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2006.07.046"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/320121"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01959219"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0046-8177(88)80325-3"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1136\/adc.76.5.454"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/17.7.1235"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2004.12.021"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1006\/nbdi.1995.0002"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1059"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1203\/01.PDR.0000113462.98851.2E"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl114"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0794-353"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.862101"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/gene.20112"},{"key":"e_1_3_2_21_2","first-page":"2378","volume":"116","year":"2006","unstructured":"Ismat FA, Xu J, Lu MM, Epstein JA. 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