{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T17:39:49Z","timestamp":1792690789372,"version":"4.5.0"},"reference-count":24,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"21","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2018,11,6]]},"abstract":"\n Background<\/jats:title>\n \n Hereditary hemorrhagic telangiectasia (\n HHT<\/jats:styled-content>\n ) is a rare genetic vascular disorder caused by mutations in endoglin (\n \n ENG<\/jats:styled-content>\n <\/jats:italic>\n ), activin receptor\u2010like kinase 1 (\n \n ACVRL<\/jats:styled-content>\n 1\n <\/jats:italic>\n ;\n \n ALK<\/jats:styled-content>\n 1\n <\/jats:italic>\n ), or\n \n SMAD<\/jats:styled-content>\n 4\n <\/jats:italic>\n . Major clinical symptoms of\n HHT<\/jats:styled-content>\n are arteriovenous malformations (\n AVM<\/jats:styled-content>\n s) found in the brain, lungs, visceral organs, and mucosal surface. Animal models harboring mutations in\n Eng<\/jats:italic>\n or\n Alk1<\/jats:italic>\n recapitulate all of these\n HHT<\/jats:styled-content>\n clinical symptoms and have been useful resources for studying mechanisms and testing potential drugs. However, animal models representing\n \n SMAD<\/jats:styled-content>\n 4\n <\/jats:italic>\n mutations have been lacking. The goal of this study is to evaluate\n Smad4<\/jats:italic>\n \u2010inducible knockout (\n iKO<\/jats:styled-content>\n ) mice as an animal model of\n HHT<\/jats:styled-content>\n and compare the phenotypes with other established\n HHT<\/jats:styled-content>\n animal models.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n Global\n Smad4<\/jats:italic>\n deletion was induced at neonatal and adult stages, and hemoglobin levels, gastrointestinal hemorrhage, and presence of aberrant arteriovenous connections were examined. Neonatal\n Smad4<\/jats:italic>\n \u2010\n iKO<\/jats:styled-content>\n mice exhibited signs of gastrointestinal bleeding and\n AVM<\/jats:styled-content>\n s in the brain, intestine, nose, and retina. The radial expansion was decreased, and\n AVM<\/jats:styled-content>\n s were detected on both distal and proximal retinal vasculature of\n Smad4<\/jats:italic>\n \u2010\n iKO<\/jats:styled-content>\n s. Aberrant smooth muscle actin staining was observed in the initial stage\n AVM<\/jats:styled-content>\n s and their connecting veins, indicating abnormal arterial flow to veins. In adult mice,\n Smad4<\/jats:italic>\n deficiency caused gastrointestinal bleeding and\n AVM<\/jats:styled-content>\n s along the gastrointestinal tract and wounded skin.\n HHT<\/jats:styled-content>\n \u2010related phenotypes of\n Smad4<\/jats:italic>\n \u2010\n iKO<\/jats:styled-content>\n s appeared to be comparable with those found in\n Alk1<\/jats:italic>\n \u2010\n iKO<\/jats:styled-content>\n and\n Eng<\/jats:italic>\n \u2010\n iKO<\/jats:styled-content>\n mice.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n These data further confirm that\n SMAD<\/jats:styled-content>\n signaling is crucial for normal arteriovenous network formation, and\n Smad4<\/jats:italic>\n \u2010\n iKO<\/jats:styled-content>\n will be an alternative animal model of\n AVM<\/jats:styled-content>\n research associated with\n HHT<\/jats:styled-content>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.118.009514","type":"journal-article","created":{"date-parts":[[2018,12,16]],"date-time":"2018-12-16T20:51:35Z","timestamp":1544993495000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":46,"title":["SMAD4 Deficiency Leads to Development of Arteriovenous Malformations in Neonatal and Adult Mice"],"prefix":"10.1161","volume":"7","author":[{"given":"Yong Hwan","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Physiology and Functional Genomics College of Medicine University of Florida Gainesville FL"},{"name":"Department of Neurobiology Barrow Neurological Institute Phoenix AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se\u2010woon","family":"Choe","sequence":"additional","affiliation":[{"name":"Department of Medical IT Convergence Engineering Kumoh National Institute of Technology Gumi Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min\u2010Young","family":"Chae","sequence":"additional","affiliation":[{"name":"Department of Physiology and Functional Genomics College of Medicine University of Florida Gainesville FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suntaek","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Physiology and Functional Genomics College of Medicine University of Florida Gainesville FL"},{"name":"Lee Gil Ya Cancer and Diabetes Institute Gachon University Incheon Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Paul","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Physiology and Functional Genomics College of Medicine University of Florida Gainesville FL"},{"name":"Department of Neurobiology Barrow Neurological Institute Phoenix AZ"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2796.1999.00398.x"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.030833"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2009.35"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(20000306)91:1<66::AID-AJMG12>3.0.CO;2-P"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2015.00001"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)15732-2"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.280.5366.1086"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/88919"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-012-0545-8"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209226"},{"key":"e_1_3_2_12_2","first-page":"3487","article-title":"Real\u2010time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia","volume":"119","author":"Park SO","year":"2009","unstructured":"Park SO, Wankhede M, Lee YJ, Choi EJ, Fliess N, Choe SW, Oh SH, Walter G, Raizada MK, Sorg BS, Oh SP. Real\u2010time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia. J Clin Invest. 2009;119:3487\u20133496.","journal-title":"J Clin Invest"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.303984"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.211037"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0098646"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep37366"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13650"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-014-9436-3"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.13683"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/gene.10029"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-08-107359"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.20284"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-02-074393"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-018-9602-0"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.033842"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.118.009514","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T10:58:08Z","timestamp":1715597888000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.118.009514"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,6]]},"references-count":24,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2018,11,6]]}},"alternative-id":["10.1161\/JAHA.118.009514"],"URL":"https:\/\/doi.org\/10.1161\/jaha.118.009514","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,6]]},"assertion":[{"value":"2018-06-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-09-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-11-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e009514"}}