{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:42:14Z","timestamp":1791999734591,"version":"4.4.0"},"reference-count":63,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,5,24]],"date-time":"2020-05-24T00:00:00Z","timestamp":1590278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL126705, R01 HL145064, R01 CA218578"],"award-info":[{"award-number":["R01 HL126705, R01 HL145064, R01 CA218578"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["17GRNT33650018"],"award-info":[{"award-number":["17GRNT33650018"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCDD"],"abstract":"<jats:p>Transforming growth factor beta3 (TGFB3) gene mutations in patients of arrhythmogenic right ventricular dysplasia\/cardiomyopathy (ARVD1) and Loeys-Dietz syndrome-5 (LDS5)\/Rienhoff syndrome are associated with cardiomyopathy, cardiac arrhythmia, cardiac fibrosis, cleft palate, aortic aneurysms, and valvular heart disease. Although the developing heart of embryos express Tgfb3, its overarching role remains unclear in cardiovascular development and disease. We used histological, immunohistochemical, and molecular analyses of Tgfb3\u2212\/\u2212 fetuses and compared them to wildtype littermate controls. The cardiovascular phenotypes were diverse with approximately two thirds of the Tgfb3\u2212\/\u2212 fetuses having one or more cardiovascular malformations, including abnormal ventricular myocardium (particularly of the right ventricle), outflow tract septal and alignment defects, abnormal aortic and pulmonary trunk walls, and thickening of semilunar and\/or atrioventricular valves. Ventricular septal defects (VSD) including the perimembranous VSDs were observed in Tgfb3\u2212\/\u2212 fetuses with myocardial defects often accompanied by the muscular type VSD. In vitro studies using TGF\u03b23-deficient fibroblasts in 3-D collagen lattice formation assays indicated that TGF\u03b23 was required for collagen matrix reorganization. Biochemical studies indicated the \u2018paradoxically\u2019 increased activation of canonical (SMAD-dependent) and noncanonical (MAP kinase-dependent) pathways. TGF\u03b23 is required for cardiovascular development to maintain a balance of canonical and noncanonical TGF\u03b2 signaling pathways.<\/jats:p>","DOI":"10.3390\/jcdd7020019","type":"journal-article","created":{"date-parts":[[2020,5,25]],"date-time":"2020-05-25T06:43:40Z","timestamp":1590389020000},"page":"19","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Transforming Growth Factor Beta3 is Required for Cardiovascular Development"],"prefix":"10.3390","volume":"7","author":[{"given":"Mrinmay","family":"Chakrabarti","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Al-Sammarraie","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1513-9844","authenticated-orcid":false,"given":"Mengistu G.","family":"Gebere","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6479-3981","authenticated-orcid":false,"given":"Aniket","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunita","family":"Chopra","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edsel A.","family":"Pe\u00f1a","sequence":"additional","affiliation":[{"name":"Department of Statistics, University of South Carolina, Columbia, SC 290208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1053-9045","authenticated-orcid":false,"given":"John F.","family":"Eberth","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"Poelmann","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana C.","family":"Gittenberger-de Groot","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9228-8096","authenticated-orcid":false,"given":"Mohamad","family":"Azhar","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29209, USA"},{"name":"William Jennings Bryan Dorn VA Medical Center, Columbia, SC 29209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/ng1295-409","article-title":"Transforming growth factor-beta 3 is required for secondary palate fusion","volume":"11","author":"Proetzel","year":"1995","journal-title":"Nat. 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