{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T01:32:06Z","timestamp":1790040726043,"version":"4.0.1"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"20","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2020,10,20]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Male patients with Marfan syndrome have a higher risk of aortic events and root dilatation compared with females. The role androgens play during Marfan syndrome aneurysm development in males remains unknown. We hypothesized that androgens potentiate transforming growth factor beta induced Erk (extracellular\u2010signal\u2010regulated kinase)\/Smad activation, contributing to aneurysm progression in males.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Aortic diameters in\n              <jats:italic>Fbn1<\/jats:italic>\n              <jats:sup>C1039G\/+<\/jats:sup>\n              and littermate wild\u2010type controls were measured at ages 6, 8, 12, and 16\u00a0weeks.\n              <jats:italic>Fbn1<\/jats:italic>\n              <jats:sup>C1039G\/+<\/jats:sup>\n              males were treated with (1) flutamide (androgen receptor blocker) or (2) vehicle control from age 6 to 16\u00a0weeks and then euthanized. p\u2010Erk1\/2, p\u2010Smad2, and matrix metalloproteinase (MMP) activity were measured in ascending\/aortic root and descending aorta specimens.\n              <jats:italic>Fbn1<\/jats:italic>\n              <jats:sup>C1039G\/+<\/jats:sup>\n              male and female ascending\/aortic root\u2010derived smooth muscle cells were utilized in vitro to measure Erk\/Smad activation and MMP\u20102 activity following dihydrotestosterone, flutamide or transforming growth factor beta 1 treatment.\n              <jats:italic>Fbn1<\/jats:italic>\n              <jats:sup>C1039G\/+<\/jats:sup>\n              males have increased aneurysm growth. p\u2010Erk1\/2 and p\u2010Smad2 were elevated in ascending\/aortic root specimens at age 16\u00a0weeks. Corresponding with enhanced Erk\/Smad signaling, MMP\u20102 activity was higher in\n              <jats:italic>Fbn1<\/jats:italic>\n              <jats:sup>C1039G\/+<\/jats:sup>\n              males. In vitro smooth muscle cell studies revealed that dihydrotestosterone potentiates transforming growth factor beta\u2010induced Erk\/Smad activation and MMP\u20102 activity, which is reversed by flutamide treatment. Finally, in vivo flutamide treatment reduced aneurysm growth via p\u2010Erk1\/2 and p\u2010Smad2 reduction in\n              <jats:italic>Fbn1<\/jats:italic>\n              <jats:sup>C1039G\/+<\/jats:sup>\n              males.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              <jats:italic>Fbn1<\/jats:italic>\n              <jats:sup>C1039G\/+<\/jats:sup>\n              males have enhanced aneurysm growth compared with females associated with enhanced p\u2010Erk1\/2 and p\u2010Smad2 activation. Mechanistically, in vitro smooth muscle cell studies suggested that dihydrotestosterone potentiates transforming growth factor beta induced Erk\/Smad activation. As biological proof of concept, flutamide treatment attenuated aneurysm growth and p\u2010Erk1\/2 and p\u2010Smad2 signaling in\n              <jats:italic>Fbn1<\/jats:italic>\n              <jats:sup>C1039G\/+<\/jats:sup>\n              males.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.119.015773","type":"journal-article","created":{"date-parts":[[2020,10,16]],"date-time":"2020-10-16T08:57:11Z","timestamp":1602838631000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":39,"title":["Androgens Accentuate TGF\u2010\u03b2 Dependent Erk\/Smad Activation During Thoracic Aortic Aneurysm Formation in Marfan Syndrome Male Mice"],"prefix":"10.1161","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9000-3410","authenticated-orcid":false,"given":"Yasushi","family":"Tashima","sequence":"first","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"},{"name":"Department of Cardiovascular Surgery Jichi Medical University Saitama Medical Center Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"He","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason Z.","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5291-5980","authenticated-orcid":false,"given":"Albert J.","family":"Pedroza","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1293-7784","authenticated-orcid":false,"given":"Ken","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5378-0261","authenticated-orcid":false,"given":"Nobu","family":"Yokoyama","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiana","family":"Iosef","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grayson","family":"Burdon","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Koyano","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery Jichi Medical University Saitama Medical Center Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0638-2025","authenticated-orcid":false,"given":"Michael P.","family":"Fischbein","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Stanford University Stanford CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197204132861502"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)67789-6"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1192149"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30068"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.841981"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehq258"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv739"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00392-016-1028-3"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2005.06.094"},{"key":"e_1_3_1_11_2","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0181166","article-title":"Sex, pregnancy and aortic disease in Marfan syndrome","volume":"9","author":"Renard M","year":"2017","unstructured":"Renard M, Muino\u2010Mosquera L, Manalo EC, Tufa S, Carlson EJ, Keene DR, De Backer J, Sakai LY. 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