{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:27:12Z","timestamp":1791296832942,"version":"4.1.0"},"reference-count":107,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2018,7,21]],"date-time":"2018-07-21T00:00:00Z","timestamp":1532131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["none"],"award-info":[{"award-number":["none"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Transforming growth factor-\u03b2 (TGF)-\u03b2 signaling plays a crucial role in the development and maintenance of various organs, including the vasculature. Accordingly, the mutations in TGF-\u03b2 signaling pathway-related genes cause heritable disorders of the connective tissue, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS), and these syndromes may affect skeletal, ocular, pulmonary, and cardiovascular systems. Aortic root aneurysms are common problems that can result in aortic dissection or rupture, which is the leading cause of sudden death in the natural history of MFS and LDS, and recent improvements in surgical treatment have improved life expectancy. However, there is currently no genotype-specific medical treatment. Accumulating evidence suggest that not only structural weakness of connective tissue but also increased TGF-\u03b2 signaling contributes to the complicated pathogenesis of aortic aneurysm formation, but a comprehensive understanding of governing molecular mechanisms remains lacking. Inhibition of angiotensin II receptor signaling and endothelial dysfunction have gained attention as a possible MFS treatment strategy, but interactions with TGF-\u03b2 signaling remain elusive. Heterozygous loss-of-function mutations in TGF-\u03b2 receptors 1 and 2 (TGFBR1 and TGFBR2) cause LDS, but TGF-\u03b2 signaling is activated in the aorta (referred to as the TGF-\u03b2 paradox) by mechanisms yet to be elucidated. In this review, we present and discuss the current understanding of molecular mechanisms responsible for aortopathies of MFS and related disorders.<\/jats:p>","DOI":"10.3390\/ijms19072125","type":"journal-article","created":{"date-parts":[[2018,7,24]],"date-time":"2018-07-24T02:58:56Z","timestamp":1532401136000},"page":"2125","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":139,"title":["TGF-\u03b2 Signaling-Related Genes and Thoracic Aortic Aneurysms and Dissections"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4818-3347","authenticated-orcid":false,"given":"Norifumi","family":"Takeda","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Hara","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8719-3997","authenticated-orcid":false,"given":"Takayuki","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsubasa","family":"Kanaya","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonoko","family":"Maemura","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Issei","family":"Komuro","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nrcardio.2009.191","article-title":"Cellular and molecular mechanisms of thoracic aortic aneurysms","volume":"6","author":"Yacoub","year":"2009","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_2","first-page":"271","article-title":"The genetics and genomics of thoracic aortic disease","volume":"2","author":"Pomianowski","year":"2013","journal-title":"Ann. Cardiothorac. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1536\/ihj.16-094","article-title":"Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys-Dietz Syndromes","volume":"57","author":"Takeda","year":"2016","journal-title":"Int. Heart J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.ijcard.2016.04.186","article-title":"The effect of losartan on progressive aortic dilatation in patients with Marfan\u2019s syndrome: A meta-analysis of prospective randomized clinical trials","volume":"217","author":"Gao","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/nrcardio.2010.31","article-title":"Marfan syndrome. Part 2: Treatment and management of patients","volume":"7","author":"Canadas","year":"2010","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1161\/01.RES.88.1.37","article-title":"Phenotypic alteration of vascular smooth muscle cells precedes elastolysis in a mouse model of Marfan syndrome","volume":"88","author":"Bunton","year":"2001","journal-title":"Circ. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.carpath.2018.01.005","article-title":"Pathogenesis of aortic wall complications in Marfan syndrome","volume":"33","author":"Grewal","year":"2018","journal-title":"Cardiovasc. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1016\/j.jtcvs.2007.12.063","article-title":"Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms, and sporadic aneurysms","volume":"136","author":"He","year":"2008","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Radonic, T., de Witte, P., Groenink, M., de Waard, V., Lutter, R., van Eijk, M., Jansen, M., Timmermans, J., Kempers, M., and Scholte, A.J. (2012). Inflammation aggravates disease severity in Marfan syndrome patients. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0032963"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/352337a0","article-title":"Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene","volume":"352","author":"Dietz","year":"1991","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1136\/jmg.2009.072785","article-title":"The revised Ghent nosology for the Marfan syndrome","volume":"47","author":"Loeys","year":"2010","journal-title":"J. Med. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1111\/ped.12423","article-title":"Pathophysiology and Japanese clinical characteristics in Marfan syndrome","volume":"56","author":"Fujita","year":"2014","journal-title":"Pediatr. Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2750","DOI":"10.1074\/jbc.M209256200","article-title":"Latent transforming growth factor beta-binding protein 1 interacts with fibrillin and is a microfibril-associated protein","volume":"278","author":"Isogai","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.str.2011.12.008","article-title":"Dissecting the fibrillin microfibril: Structural insights into organization and function","volume":"20","author":"Jensen","year":"2012","journal-title":"Structure"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1038\/nrm2262","article-title":"Extracellular control of TGFbeta signalling in vascular development and disease","volume":"8","author":"Arthur","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/ng1116","article-title":"Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome","volume":"33","author":"Neptune","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1161\/CIRCULATIONAHA.108.841981","article-title":"Circulating transforming growth factor-beta in Marfan syndrome","volume":"120","author":"Matt","year":"2009","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1203\/PDR.0b013e3182097219","article-title":"Prognosis factors in probands with an FBN1 mutation diagnosed before the age of 1 year","volume":"69","author":"Stheneur","year":"2011","journal-title":"Pediatr. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/ajmg.a.30979","article-title":"Severe infantile Marfan syndrome versus neonatal Marfan syndrome","volume":"139","author":"Hennekam","year":"2005","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1086\/520125","article-title":"Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: An international study","volume":"81","author":"Faivre","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1086\/341581","article-title":"Premature termination mutations in FBN1: Distinct effects on differential allelic expression and on protein and clinical phenotypes","volume":"71","author":"Schrijver","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1517\/21678707.2014.950223","article-title":"Diagnosis and genetics of Marfan syndrome","volume":"2","author":"Franken","year":"2014","journal-title":"Expert Opin. Orphan Drugs"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/gim.2014.91","article-title":"Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events","volume":"17","author":"Baudhuin","year":"2015","journal-title":"Genet. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3285","DOI":"10.1093\/eurheartj\/ehv739","article-title":"Genotype impacts survival in Marfan syndrome","volume":"37","author":"Franken","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1136\/heartjnl-2016-310631","article-title":"Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome","volume":"103","author":"Franken","year":"2017","journal-title":"Heart"},{"key":"ref_26","first-page":"e002058","article-title":"Impact of Pathogenic FBN1 Variant Types on the Progression of Aortic Disease in Patients With Marfan Syndrome","volume":"11","author":"Takeda","year":"2018","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1083\/jcb.200608167","article-title":"Fibrillin-1 regulates the bioavailability of TGFbeta1","volume":"176","author":"Chaudhry","year":"2007","journal-title":"J. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"32924","DOI":"10.1074\/jbc.M405239200","article-title":"Consequences of cysteine mutations in calcium-binding epidermal growth factor modules of fibrillin-1","volume":"279","author":"Vollbrandt","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7368","DOI":"10.1074\/jbc.272.11.7368","article-title":"Calcium determines the shape of fibrillin","volume":"272","author":"Reinhardt","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/ejhg.2010.174","article-title":"The clinical spectrum of complete FBN1 allele deletions","volume":"19","author":"Hamel","year":"2011","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3819","DOI":"10.1073\/pnas.96.7.3819","article-title":"Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1","volume":"96","author":"Pereira","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1172\/JCI200422715","article-title":"TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome","volume":"114","author":"Ng","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1172\/JCI200420641","article-title":"Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome","volume":"114","author":"Judge","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Cikach, F.S., Koch, C.D., Mead, T.J., Galatioto, J., Willard, B.B., Emerton, K.B., Eagleton, M.J., Blackstone, E.H., Ramirez, F., and Roselli, E.E. (2018). Massive aggrecan and versican accumulation in thoracic aortic aneurysm and dissection. JCI Insight, 3.","DOI":"10.1172\/jci.insight.97167"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1126\/science.1124287","article-title":"Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome","volume":"312","author":"Habashi","year":"2006","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1126\/science.1192149","article-title":"Noncanonical TGFbeta signaling contributes to aortic aneurysm progression in Marfan syndrome mice","volume":"332","author":"Holm","year":"2011","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s00441-011-1201-y","article-title":"Non-Smad signaling pathways","volume":"347","author":"Mu","year":"2012","journal-title":"Cell Tissue Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/978-1-4939-2966-5_23","article-title":"The Role of Ubiquitination to Determine Non-Smad Signaling Responses","volume":"1344","author":"Gudey","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref_39","first-page":"42","article-title":"Angiotensin II Receptor Antagonism Reduces Transforming Growth Factor Beta and Smad Signaling in Thoracic Aortic Aneurysm","volume":"13","author":"Nataatmadja","year":"2013","journal-title":"Ochsner J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1126\/science.1192152","article-title":"Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism","volume":"332","author":"Habashi","year":"2011","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.athoracsur.2016.10.077","article-title":"A Novel Murine Model of Marfan Syndrome Accelerates Aortopathy and Cardiomyopathy","volume":"104","author":"Cavanaugh","year":"2017","journal-title":"Ann. Thorac. Surg."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3491","DOI":"10.1093\/eurheartj\/eht334","article-title":"Losartan reduces aortic dilatation rate in adults with Marfan syndrome: A randomized controlled trial","volume":"34","author":"Groenink","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1056\/NEJMoa1404731","article-title":"Atenolol versus losartan in children and young adults with Marfan\u2019s syndrome","volume":"371","author":"Lacro","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1093\/eurheartj\/ehv575","article-title":"Efficacy of losartan vs. atenolol for the prevention of aortic dilation in Marfan syndrome: A randomized clinical trial","volume":"37","author":"Forteza","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1097\/FJC.0000000000000560","article-title":"The Effect of a Nonpeptide Angiotensin II Type 2 Receptor Agonist, Compound 21, on Aortic Aneurysm Growth in a Mouse Model of Marfan Syndrome","volume":"71","author":"Verbrugghe","year":"2018","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"H1516","DOI":"10.1152\/ajpheart.00291.2015","article-title":"The role of beta-arrestin2-dependent signaling in thoracic aortic aneurysm formation in a murine model of Marfan syndrome","volume":"309","author":"Wisler","year":"2015","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1161\/ATVBAHA.117.310609","article-title":"Cell Type-Specific Contributions of the Angiotensin II Type 1a Receptor to Aorta Homeostasis and Aneurysmal Disease-Brief Report","volume":"38","author":"Galatioto","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1007\/s00380-013-0393-3","article-title":"Impairment of flow-mediated dilation correlates with aortic dilation in patients with Marfan syndrome","volume":"29","author":"Takata","year":"2014","journal-title":"Heart Vessel."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1016\/j.amjcard.2018.01.016","article-title":"Influence of Aortic Stiffness on Aortic-Root Growth Rate and Outcome in Patients with the Marfan Syndrome","volume":"121","author":"Levine","year":"2018","journal-title":"Am. J. Cardiol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Loeper, F., Oosterhof, J., van den Dorpel, M., van der Linde, D., Lu, Y., Robertson, E., Hambly, B., and Jeremy, R. (2016). Ventricular-Vascular Coupling in Marfan and Non-Marfan Aortopathies. J. Am. Heart Assoc., 5.","DOI":"10.1161\/JAHA.116.003705"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.ajpath.2017.11.006","article-title":"Inhibition of Marfan Syndrome Aortic Root Dilation by Losartan: Role of Angiotensin II Receptor Type 1-Independent Activation of Endothelial Function","volume":"188","author":"Sellers","year":"2018","journal-title":"Am. J. Pathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.ijcard.2010.04.077","article-title":"Evidence for oxidative stress in plasma of patients with Marfan syndrome","volume":"145","author":"Fiorillo","year":"2010","journal-title":"Int. J. Cardiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.vph.2009.10.005","article-title":"Vasomotor dysfunction in the thoracic aorta of Marfan syndrome is associated with accumulation of oxidative stress","volume":"52","author":"Yang","year":"2010","journal-title":"Vasc. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.freeradbiomed.2018.02.023","article-title":"Redox stress in Marfan syndrome: Dissecting the role of the NADPH oxidase NOX4 in aortic aneurysm","volume":"118","author":"Meirelles","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/nm.4266","article-title":"Nitric oxide mediates aortic disease in mice deficient in the metalloprotease Adamts1 and in a mouse model of Marfan syndrome","volume":"23","author":"Oller","year":"2017","journal-title":"Nat. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"S168","DOI":"10.1161\/CIRCULATIONAHA.110.012187","article-title":"Pravastatin reduces Marfan aortic dilation","volume":"124","author":"McLoughlin","year":"2011","journal-title":"Circulation"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1161\/ATVBAHA.116.307841","article-title":"Resveratrol Inhibits Aortic Root Dilatation in the Fbn1C1039G\/+ Marfan Mouse Model","volume":"36","author":"Hibender","year":"2016","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1093\/eurheartj\/ehu041","article-title":"Elastin fragmentation in atherosclerotic mice leads to intraplaque neovascularization, plaque rupture, myocardial infarction, stroke, and sudden death","volume":"36","author":"Schrijvers","year":"2015","journal-title":"Eur. Heart J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e000476","DOI":"10.1161\/JAHA.113.000476","article-title":"IL-6 regulates extracellular matrix remodeling associated with aortic dilation in a fibrillin-1 hypomorphic mgR\/mgR mouse model of severe Marfan syndrome","volume":"3","author":"Ju","year":"2014","journal-title":"J. Am. Heart Assoc."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1136\/hrt.82.3.286","article-title":"Cystic medial degeneration of the aorta is associated with p53 accumulation, Bax upregulation, apoptotic cell death, and cell proliferation","volume":"82","author":"Ihling","year":"1999","journal-title":"Heart"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e73","DOI":"10.1161\/CIRCRESAHA.108.174367","article-title":"Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in marfan syndrome through the inhibition of matrix metalloproteinase-2 and -9","volume":"102","author":"Chung","year":"2008","journal-title":"Circ. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1161\/ATVBAHA.114.304364","article-title":"Enhanced caspase activity contributes to aortic wall remodeling and early aneurysm development in a murine model of Marfan syndrome","volume":"35","author":"Emrich","year":"2015","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"831641","DOI":"10.1155\/2015\/831641","article-title":"MicroRNAs: Novel Players in Aortic Aneurysm","volume":"2015","author":"Fu","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1097\/HCO.0000000000000216","article-title":"Abdominal aortic aneurysm: Novel mechanisms and therapies","volume":"30","author":"Davis","year":"2015","journal-title":"Curr. Opin. Cardiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1055\/s-0037-1604083","article-title":"Characterization of micro-RNA Profile in the Blood of Patients with Marfan\u2019s Syndrome","volume":"66","author":"Ludwig","year":"2018","journal-title":"Thorac. Cardiovasc. Surg."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1161\/CIRCRESAHA.111.253740","article-title":"miR-29b participates in early aneurysm development in Marfan syndrome","volume":"110","author":"Merk","year":"2012","journal-title":"Circ. Res."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Okamura, H., Emrich, F., Trojan, J., Chiu, P., Dalal, A.R., Arakawa, M., Sato, T., Penov, K., Koyano, T., and Pedroza, A. (2017). Long-term miR-29b suppression reduces aneurysm formation in a Marfan mouse model. Physiol. Rep., 5.","DOI":"10.14814\/phy2.13257"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1161\/ATVBAHA.114.305150","article-title":"Dimorphic effects of transforming growth factor-beta signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome","volume":"35","author":"Cook","year":"2015","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1038\/ng.2349","article-title":"Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm","volume":"44","author":"Lindsay","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1172\/JCI69942","article-title":"Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis","volume":"124","author":"Li","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2647","DOI":"10.1161\/ATVBAHA.115.306573","article-title":"Postnatal Deletion of the Type II Transforming Growth Factor-beta Receptor in Smooth Muscle Cells Causes Severe Aortopathy in Mice","volume":"35","author":"Hu","year":"2015","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1056\/NEJMoa055695","article-title":"Aneurysm syndromes caused by mutations in the TGF-beta receptor","volume":"355","author":"Loeys","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/gim.2014.11","article-title":"Loeys-Dietz syndrome: A primer for diagnosis and management","volume":"16","author":"MacCarrick","year":"2014","journal-title":"Genet. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1038\/ng1392","article-title":"Heterozygous TGFBR2 mutations in Marfan syndrome","volume":"36","author":"Mizuguchi","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/ng1511","article-title":"A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2","volume":"37","author":"Loeys","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/ng.744","article-title":"Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis","volume":"43","author":"Oldenburg","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1161\/CIRCRESAHA.111.248161","article-title":"Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms","volume":"109","author":"Regalado","year":"2011","journal-title":"Circ. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/ng.2348","article-title":"TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome","volume":"44","author":"Boileau","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1016\/j.jacc.2015.01.040","article-title":"Mutations in a TGF-beta ligand, TGFB3, cause syndromic aortic aneurysms and dissections","volume":"65","author":"Gillis","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1038\/ncb1780","article-title":"The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner","volume":"10","author":"Sorrentino","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"4371","DOI":"10.1128\/MCB.23.12.4371-4385.2003","article-title":"Heart and liver defects and reduced transforming growth factor beta2 sensitivity in transforming growth factor beta type III receptor-deficient embryos","volume":"23","author":"Stenvers","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"5269","DOI":"10.1242\/dev.00708","article-title":"Conditional inactivation of Tgfbr2 in cranial neural crest causes cleft palate and calvaria defects","volume":"130","author":"Ito","year":"2003","journal-title":"Development"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.ydbio.2006.05.030","article-title":"Epithelial and ectomesenchymal role of the type I TGF-beta receptor ALK5 during facial morphogenesis and palatal fusion","volume":"296","author":"Dudas","year":"2006","journal-title":"Dev. Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1172\/JCI61498","article-title":"Modulation of noncanonical TGF-beta signaling prevents cleft palate in Tgfbr2 mutant mice","volume":"122","author":"Iwata","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"4340","DOI":"10.1242\/jcs.074773","article-title":"Quantitative analysis of TGFBR2 mutations in Marfan-syndrome-related disorders suggests a correlation between phenotypic severity and Smad signaling activity","volume":"123","author":"Horbelt","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"150","DOI":"10.3109\/10799893.2012.664553","article-title":"TGFBR1 mutations associated with Loeys-Dietz syndrome are inactivating","volume":"32","author":"Cardoso","year":"2012","journal-title":"J. Recept. Signal Transduct. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/ng.2366","article-title":"The paradoxical TGF-beta vasculopathies","volume":"44","author":"Akhurst","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1172\/JCI69666","article-title":"Angiotensin II-dependent TGF-beta signaling contributes to Loeys-Dietz syndrome vascular pathogenesis","volume":"124","author":"Gallo","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_89","first-page":"157","article-title":"Multiple self-healing squamous epithelioma","volume":"7","author":"Wallace","year":"1971","journal-title":"Birth Defects Orig. Artic. Ser."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1038\/ng.780","article-title":"Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1","volume":"43","author":"Goudie","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Fujiwara, T., Takeda, N., Hara, H., Morita, H., Kishihara, J., Inuzuka, R., Yagi, H., Maemura, S., Toko, H., and Harada, M. (2018). Distinct variants affecting differential splicing of TGFBR1 exon 5 cause either Loeys-Dietz syndrome or multiple self-healing squamous epithelioma. Eur. J. Hum. Genet.","DOI":"10.1038\/s41431-018-0127-1"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.ebiom.2016.09.006","article-title":"Defective Connective Tissue Remodeling in SMAD3 Mice Leads to Accelerated Aneurysmal Growth Through Disturbed Downstream TGF-beta Signaling","volume":"12","author":"Robertus","year":"2016","journal-title":"EBioMedicine"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1097\/BRS.0b013e3181a3c7c7","article-title":"A continuous observation of the degenerative process in the intervertebral disc of SMAD3 gene knock-out mice","volume":"34","author":"Li","year":"2009","journal-title":"Spine"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1038\/ng.2421","article-title":"Mutations in the TGF-beta repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm","volume":"44","author":"Doyle","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1038\/ejhg.2014.61","article-title":"The SMAD-binding domain of SKI: A hotspot for de novo mutations causing Shprintzen-Goldberg syndrome","volume":"23","author":"Schepers","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2196","DOI":"10.1101\/gad.13.17.2196","article-title":"The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling","volume":"13","author":"Luo","year":"1999","journal-title":"Genes Dev."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1101\/gad.13.4.412","article-title":"Ski is a component of the histone deacetylase complex required for transcriptional repression by Mad and thyroid hormone receptor","volume":"13","author":"Nomura","year":"1999","journal-title":"Genes Dev."},{"key":"ref_98","first-page":"1329","article-title":"Abnormal muscle mechanosignaling triggers cardiomyopathy in mice with Marfan syndrome","volume":"124","author":"Cook","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"H290","DOI":"10.1152\/ajpheart.00354.2015","article-title":"Cardiac remodeling in the mouse model of Marfan syndrome develops into two distinctive phenotypes","volume":"310","author":"Tae","year":"2016","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Rouf, R., MacFarlane, E.G., Takimoto, E., Chaudhary, R., Nagpal, V., Rainer, P.P., Bindman, J.G., Gerber, E.E., Bedja, D., and Schiefer, C. (2017). Nonmyocyte ERK1\/2 signaling contributes to load-induced cardiomyopathy in Marfan mice. JCI Insight, 2.","DOI":"10.1172\/jci.insight.91588"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1161\/CIRCULATIONAHA.104.493569","article-title":"Cardiovascular problems in pregnant women with marfan syndrome","volume":"119","author":"Goland","year":"2009","journal-title":"Circulation"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1097\/AOG.0b013e3182107310","article-title":"Marfan syndrome and aortic dissection in pregnancy","volume":"117","author":"Houston","year":"2011","journal-title":"Obstet. Gynecol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.ijcard.2015.07.109","article-title":"A novel mutation of TGFBR2 causing Loeys-Dietz syndrome complicated with pregnancy-related fatal cervical arterial dissections","volume":"201","author":"Fujita","year":"2015","journal-title":"Int. J. Cardiol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1111\/1471-0528.14635","article-title":"Peripartum type B aortic dissection in patients with Marfan syndrome who underwent aortic root replacement: A case series study","volume":"125","author":"Sayama","year":"2018","journal-title":"BJOG"},{"key":"ref_105","first-page":"e002185","article-title":"Looking for the Missing Links: Challenges in the Search for Genotype-Phenotype Correlation in Marfan Syndrome","volume":"11","author":"Campens","year":"2018","journal-title":"Circ. Genom. Precis. Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1073\/pnas.1113442109","article-title":"Skeletogenic phenotype of human Marfan embryonic stem cells faithfully phenocopied by patient-specific induced-pluripotent stem cells","volume":"109","author":"Quarto","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/ng.3723","article-title":"An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death","volume":"49","author":"Granata","year":"2017","journal-title":"Nat. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/7\/2125\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:13:33Z","timestamp":1760195613000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/7\/2125"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,7,21]]},"references-count":107,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2018,7]]}},"alternative-id":["ijms19072125"],"URL":"https:\/\/doi.org\/10.3390\/ijms19072125","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,7,21]]}}}