{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:28:54Z","timestamp":1790947734332,"version":"4.1.0"},"reference-count":141,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T00:00:00Z","timestamp":1624320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>\n                    NOTCH intercellular signaling mediates the communications between adjacent cells involved in multiple biological processes essential for tissue morphogenesis and homeostasis. The\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    mutations are the first identified human genetic variants that cause congenital bicuspid aortic valve (BAV) and calcific aortic valve disease (CAVD). Genetic variants affecting other genes in the NOTCH signaling pathway may also contribute to the development of BAV and the pathogenesis of CAVD. While CAVD occurs commonly in the elderly population with tri-leaflet aortic valve, patients with BAV have a high risk of developing CAVD at a young age. This observation indicates an important role of NOTCH signaling in the postnatal homeostasis of the aortic valve, in addition to its prenatal functions during aortic valve development. Over the last decade, animal studies, especially with the mouse models, have revealed detailed information in the developmental etiology of congenital aortic valve defects. In this review, we will discuss the molecular and cellular aspects of aortic valve development and examine the embryonic pathogenesis of BAV. We will focus our discussions on the NOTCH signaling during the endocardial-to-mesenchymal transformation (EMT) and the post-EMT remodeling of the aortic valve. We will further examine the involvement of the NOTCH mutations in the postnatal development of CAVD. We will emphasize the deleterious impact of the embryonic valve defects on the homeostatic mechanisms of the adult aortic valve for the purpose of identifying the potential therapeutic targets for disease intervention.\n                  <\/jats:p>","DOI":"10.3389\/fcvm.2021.682298","type":"journal-article","created":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T00:19:53Z","timestamp":1624321193000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":44,"title":["NOTCH Signaling in Aortic Valve Development and Calcific Aortic Valve Disease"],"prefix":"10.3389","volume":"8","author":[{"given":"Yidong","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingruo","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1146\/annurev-physiol-022516-034001","article-title":"Developmental mechanisms of aortic valve malformation and disease","volume":"79","author":"Wu","year":"2017","journal-title":"Annu Rev Physiol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"162","DOI":"10.3389\/fcvm.2018.00162","article-title":"The genetic regulation of aortic valve development and calcific disease","volume":"5","author":"Menon","year":"2018","journal-title":"Front Cardiovasc Med"},{"key":"B3","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1161\/CIRCRESAHA.112.300154","article-title":"Hemodynamic and cellular response feedback in calcific aortic valve disease","volume":"113","author":"Gould","year":"2013","journal-title":"Circ Res"},{"key":"B4","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1089\/ars.2015.6554","article-title":"Shear-Sensitive genes in aortic valve endothelium","volume":"25","author":"Fernandez Esmerats","year":"2016","journal-title":"Antioxid Redox Signal"},{"key":"B5","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1161\/CIRCRESAHA.113.300155","article-title":"Molecular and cellular aspects of calcific aortic valve disease","volume":"113","author":"Towler","year":"2013","journal-title":"Circ Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1016\/j.cjca.2014.03.029","article-title":"Basic mechanisms of calcific aortic valve disease","volume":"30","author":"Mathieu","year":"2014","journal-title":"Can J Cardiol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"2387","DOI":"10.1161\/ATVBAHA.114.302523","article-title":"Calcific aortic valve disease: a consensus summary from the Alliance of Investigators on calcific aortic valve disease","volume":"34","author":"Yutzey","year":"2014","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.1016\/S0140-6736(16)00586-9","article-title":"Management strategies and future challenges for aortic valve disease","volume":"387","author":"Bonow","year":"2016","journal-title":"Lancet"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2618","DOI":"10.1093\/eurheartj\/ehx653","article-title":"Calcific aortic valve stenosis: hard disease in the heart: a biomolecular approach towards diagnosis and treatment","volume":"39","author":"Peeters","year":"2018","journal-title":"Eur Heart J"},{"key":"B10","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.yjmcc.2019.05.016","article-title":"Development of calcific aortic valve disease: do we know enough for new clinical trials?","volume":"132","author":"Kostyunin","year":"2019","journal-title":"J Mol Cell Cardiol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e28","DOI":"10.1161\/01.cir.0000442015.53336.12","article-title":"American Heart Association Statistics C and Stroke Statistics S. Heart disease and stroke statistics\u22122014 update: a report from the American Heart Association","volume":"129","author":"Go","year":"2014","journal-title":"Circulation"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1016\/S0140-6736(06)69208-8","article-title":"Burden of valvular heart diseases: a population-based study","volume":"368","author":"Nkomo","year":"2006","journal-title":"Lancet"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1890","DOI":"10.1016\/S0735-1097(02)01886-7","article-title":"The incidence of congenital heart disease","volume":"39","author":"Hoffman","year":"2002","journal-title":"J Am Coll Cardiol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1177\/2047487312451238","article-title":"Prevalence of calcific aortic valve disease in the elderly and associated risk factors: a population-based study in a Mediterranean area","volume":"20","author":"Ferreira-Gonzalez","year":"2013","journal-title":"Eur J Prev Cardiol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1136\/heartjnl-2014-305509","article-title":"Interactions between inflammatory activation and endothelial dysfunction selectively modulate valve disease progression in patients with bicuspid aortic valve","volume":"100","author":"Ali","year":"2014","journal-title":"Heart"},{"key":"B16","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1161\/CIRCULATIONAHA.113.003026","article-title":"Bicuspid aortic cusp fusion morphology alters aortic three-dimensional outflow patterns, wall shear stress, and expression of aortopathy","volume":"129","author":"Mahadevia","year":"2014","journal-title":"Circulation"},{"key":"B17","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1093\/ejcts\/ezy312","article-title":"Haemodynamic assessment of bicuspid aortic valve aortopathy: a systematic review of the current literature","volume":"55","author":"Edlin","year":"2019","journal-title":"Eur J Cardiothorac Surg"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.3389\/fphys.2020.01015","article-title":"Bicuspid aortic valve and endothelial dysfunction: current evidence and potential therapeutic targets","volume":"11","author":"Antequera-Gonzalez","year":"2020","journal-title":"Front Physiol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1126\/science.6844926","article-title":"Neural crest cells contribute to normal aorticopulmonary septation","volume":"220","author":"Kirby","year":"1983","journal-title":"Science"},{"key":"B20","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1161\/01.RES.0000141429.13560.cb","article-title":"Lineage and morphogenetic analysis of the cardiac valves","volume":"95","author":"de Lange","year":"2004","journal-title":"Circ Res"},{"key":"B21","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1172\/JCI44244","article-title":"Cardiac neural crest orchestrates remodeling and functional maturation of mouse semilunar valves","volume":"121","author":"Jain","year":"2011","journal-title":"J Clin Invest"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1016\/j.yjmcc.2012.01.013","article-title":"The secondary heart field is a new site of calcineurin\/Nfatc1 signaling for semilunar valve development","volume":"52","author":"Lin","year":"2012","journal-title":"J Mol Cell Cardiol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1038\/nature06801","article-title":"The developmental genetics of congenital heart disease","volume":"451","author":"Bruneau","year":"2008","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1146\/annurev-physiol-012110-142145","article-title":"Heart valve structure and function in development and disease","volume":"73","author":"Hinton","year":"2011","journal-title":"Annu Rev Physiol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"3277","DOI":"10.1242\/dev.063495","article-title":"Partitioning the heart: mechanisms of cardiac septation and valve development","volume":"139","author":"Lin","year":"2012","journal-title":"Development"},{"key":"B26","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/nrg2279","article-title":"The multifaceted role of Notch in cardiac development and disease","volume":"9","author":"High","year":"2008","journal-title":"Nat Rev Genet"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1161\/CIRCRESAHA.108.174318","article-title":"Notch signaling in cardiac development","volume":"102","author":"Niessen","year":"2008","journal-title":"Circ Res"},{"key":"B28","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1007\/s00246-008-9368-z","article-title":"Notch signaling in cardiac development and disease","volume":"30","author":"de la Pompa","year":"2009","journal-title":"Pediatr Cardiol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/S0070-2153(10)92011-5","article-title":"Notch signaling in cardiac development and disease","volume":"92","author":"MacGrogan","year":"2010","journal-title":"Curr Top Dev Biol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1002\/bdra.20815","article-title":"Notch signaling in cardiac valve development and disease","volume":"91","author":"MacGrogan","year":"2011","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"key":"B31","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/978-4-431-54628-3_53","article-title":"Notch signaling in aortic valve development and disease.","volume-title":"Etiology and Morphogenesis of Congenital Heart Disease: From Gene Function and Cellular Interaction to Morphology","author":"Garg","year":"2016"},{"key":"B32","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/nature03940","article-title":"Mutations in NOTCH1 cause aortic valve disease","volume":"437","author":"Garg","year":"2005","journal-title":"Nature"},{"key":"B33","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1242\/dev.113.3.891","article-title":"Clonal analysis of epiblast fate during germ layer formation in the mouse embryo","volume":"113","author":"Lawson","year":"1991","journal-title":"Development"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.1242\/dev.124.9.1631","article-title":"The allocation of epiblast cells to the embryonic heart and other mesodermal lineages: the role of ingression and tissue movement during gastrulation","volume":"124","author":"Tam","year":"1997","journal-title":"Development"},{"key":"B35","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1146\/annurev.cellbio.23.090506.123331","article-title":"Heart field: from mesoderm to heart tube","volume":"23","author":"Abu-Issa","year":"2007","journal-title":"Annu Rev Cell Dev Biol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0070-2153(10)90001-X","article-title":"How to make a heart: the origin and regulation of cardiac progenitor cells","volume":"90","author":"Vincent","year":"2010","journal-title":"Curr Top Dev Biol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/S1534-5807(01)00040-5","article-title":"The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm","volume":"1","author":"Kelly","year":"2001","journal-title":"Dev Cell"},{"key":"B38","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1006\/dbio.2001.0409","article-title":"The outflow tract of the heart is recruited from a novel heart-forming field","volume":"238","author":"Mjaatvedt","year":"2001","journal-title":"Dev Biol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"3179","DOI":"10.1242\/dev.128.16.3179","article-title":"Conotruncal myocardium arises from a secondary heart field","volume":"128","author":"Waldo","year":"2001","journal-title":"Development"},{"key":"B40","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1016\/S1534-5807(03)00363-0","article-title":"Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart","volume":"5","author":"Cai","year":"2003","journal-title":"Dev Cell"},{"key":"B41","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1161\/01.RES.0000141146.95728.da","article-title":"Heart valve development: endothelial cell signaling and differentiation","volume":"95","author":"Armstrong","year":"2004","journal-title":"Circ Res"},{"key":"B42","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1161\/CIRCRESAHA.109.201566","article-title":"Heart valve development: regulatory networks in development and disease","volume":"105","author":"Combs","year":"2009","journal-title":"Circ Res"},{"key":"B43","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1002\/bdra.20799","article-title":"Molecular and developmental mechanisms of congenital heart valve disease","volume":"91","author":"Lincoln","year":"2011","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1159\/000147845","article-title":"Epithelial-mesenchymal transformations in early avian heart development","volume":"156","author":"Markwald","year":"1996","journal-title":"Acta Anat"},{"key":"B45","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1007\/s00109-003-0456-5","article-title":"Form and function of developing heart valves: coordination by extracellular matrix and growth factor signaling","volume":"81","author":"Schroeder","year":"2003","journal-title":"J Mol Med"},{"key":"B46","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1002\/dvdy.20051","article-title":"Development of heart valve leaflets and supporting apparatus in chicken and mouse embryos","volume":"230","author":"Lincoln","year":"2004","journal-title":"Dev Dyn"},{"key":"B47","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/S0074-7696(05)43005-3","article-title":"Cell biology of cardiac cushion development","volume":"243","author":"Person","year":"2005","journal-title":"Int Rev Cytol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.devcel.2012.06.006","article-title":"Tbx5-hedgehog molecular networks are essential in the second heart field for atrial septation","volume":"23","author":"Xie","year":"2012","journal-title":"Dev Cell"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e002508","DOI":"10.1161\/JAHA.115.002508","article-title":"Rac1 Signaling is required for anterior second heart field cellular organization and cardiac outflow tract development","volume":"5","author":"Leung","year":"2015","journal-title":"J Am Heart Assoc"},{"key":"B50","doi-asserted-by":"publisher","first-page":"e34110","DOI":"10.7554\/eLife.34110","article-title":"A novel source of arterial valve cells linked to bicuspid aortic valve without raphe in mice","volume":"7","author":"Eley","year":"2018","journal-title":"Elife"},{"key":"B51","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1002\/dvdy.24641","article-title":"Intercalated cushion cells within the cardiac outflow tract are derived from the myocardial troponin T type 2 (Tnnt2) Cre lineage","volume":"247","author":"Mifflin","year":"2018","journal-title":"Dev Dyn"},{"key":"B52","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1093\/eurheartj\/ehv520","article-title":"Notch-Tnf signalling is required for development and homeostasis of arterial valves","volume":"38","author":"Wang","year":"2017","journal-title":"Eur Heart J"},{"key":"B53","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1161\/01.RES.77.1.1","article-title":"Molecular regulation of atrioventricular valvuloseptal morphogenesis","volume":"77","author":"Eisenberg","year":"1995","journal-title":"Circ Res"},{"key":"B54","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1006\/dbio.2000.9927","article-title":"Expression of chick Tbx-2, Tbx-3, and Tbx-5 genes during early heart development: evidence for BMP2 induction of Tbx2","volume":"228","author":"Yamada","year":"2000","journal-title":"Dev Biol"},{"key":"B55","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1006\/dbio.1999.9211","article-title":"TGFbeta2 and TGFbeta3 have separate and sequential activities during epithelial-mesenchymal cell transformation in the embryonic heart","volume":"208","author":"Boyer","year":"1999","journal-title":"Dev Biol"},{"key":"B56","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1006\/dbio.2002.0731","article-title":"Temporal and distinct TGFbeta ligand requirements during mouse and avian endocardial cushion morphogenesis","volume":"248","author":"Camenisch","year":"2002","journal-title":"Dev Biol"},{"key":"B57","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1038\/ng1295-415","article-title":"Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction","volume":"11","author":"Kaartinen","year":"1995","journal-title":"Nat Genet"},{"key":"B58","doi-asserted-by":"publisher","first-page":"5601","DOI":"10.1242\/dev.02156","article-title":"Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning","volume":"132","author":"Ma","year":"2005","journal-title":"Development"},{"key":"B59","doi-asserted-by":"publisher","first-page":"e60244","DOI":"10.1371\/journal.pone.0060244","article-title":"Endocardial to myocardial notch-wnt-bmp axis regulates early heart valve development","volume":"8","author":"Wang","year":"2013","journal-title":"PLoS ONE"},{"key":"B60","doi-asserted-by":"publisher","first-page":"2362","DOI":"10.1101\/gad.1124803","article-title":"An essential role of Bmp4 in the atrioventricular septation of the mouse heart","volume":"17","author":"Jiao","year":"2003","journal-title":"Genes Dev"},{"key":"B61","doi-asserted-by":"publisher","first-page":"3200","DOI":"10.1002\/dvdy.21743","article-title":"BMP4 is required in the anterior heart field and its derivatives for endocardial cushion remodeling, outflow tract septation, and semilunar valve development","volume":"237","author":"McCulley","year":"2008","journal-title":"Dev Dyn"},{"key":"B62","doi-asserted-by":"publisher","first-page":"3493","DOI":"10.1172\/JCI42666","article-title":"Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation","volume":"120","author":"Luna-Zurita","year":"2010","journal-title":"J Clin Invest"},{"key":"B63","doi-asserted-by":"publisher","first-page":"5041","DOI":"10.1242\/dev.01378","article-title":"Tbx2 is essential for patterning the atrioventricular canal and for morphogenesis of the outflow tract during heart development","volume":"131","author":"Harrelson","year":"2004","journal-title":"Development"},{"key":"B64","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1007\/s00018-011-0884-2","article-title":"Tbx2 and Tbx3 induce atrioventricular myocardial development and endocardial cushion formation","volume":"69","author":"Singh","year":"2012","journal-title":"Cell Mol Life Sci"},{"key":"B65","doi-asserted-by":"publisher","first-page":"148","DOI":"10.2174\/157340308785160552","article-title":"Notch signaling in cardiovascular disease and calcification","volume":"4","author":"Rusanescu","year":"2008","journal-title":"Curr Cardiol Rev"},{"key":"B66","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1038\/s41569-018-0100-2","article-title":"Notch and interacting signalling pathways in cardiac development, disease, and regeneration","volume":"15","author":"MacGrogan","year":"2018","journal-title":"Nat Rev Cardiol"},{"key":"B67","doi-asserted-by":"publisher","first-page":"13638","DOI":"10.1074\/jbc.M802027200","article-title":"Roles of Pofut1 and O-fucose in mammalian Notch signaling","volume":"283","author":"Stahl","year":"2008","journal-title":"J Biol Chem"},{"key":"B68","doi-asserted-by":"publisher","first-page":"5234","DOI":"10.1073\/pnas.0831126100","article-title":"Protein O-fucosyltransferase 1 is an essential component of Notch signaling pathways","volume":"100","author":"Shi","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"B69","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1016\/j.cell.2009.03.025","article-title":"The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis","volume":"137","author":"Benedito","year":"2009","journal-title":"Cell"},{"key":"B70","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.devcel.2009.03.010","article-title":"Notch signaling: the core pathway and its posttranslational regulation","volume":"16","author":"Fortini","year":"2009","journal-title":"Dev Cell"},{"key":"B71","doi-asserted-by":"publisher","first-page":"3865","DOI":"10.1242\/dev.127.17.3865","article-title":"Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis","volume":"127","author":"Rones","year":"2000","journal-title":"Development"},{"key":"B72","doi-asserted-by":"publisher","first-page":"4018","DOI":"10.1073\/pnas.0438008100","article-title":"Recombination signal sequence-binding protein Jkappa alters mesodermal cell fate decisions by suppressing cardiomyogenesis","volume":"100","author":"Schroeder","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"B73","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/j.ydbio.2005.09.015","article-title":"Subdividing the embryo: a role for Notch signaling during germ layer patterning in Xenopus laevis","volume":"288","author":"Contakos","year":"2005","journal-title":"Dev Biol"},{"key":"B74","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1161\/01.RES.0000226497.52052.2a","article-title":"Induction of cardiogenesis in embryonic stem cells via downregulation of Notch1 signaling","volume":"98","author":"Nemir","year":"2006","journal-title":"Circ Res"},{"key":"B75","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1126\/science.aao4174","article-title":"Defining the earliest step of cardiovascular lineage segregation by single-cell RNA-seq","volume":"359","author":"Lescroart","year":"2018","journal-title":"Science"},{"key":"B76","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.devcel.2006.12.011","article-title":"Notch signaling is essential for ventricular chamber development","volume":"12","author":"Grego-Bessa","year":"2007","journal-title":"Dev Cell"},{"key":"B77","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1101\/gad.276304","article-title":"Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation","volume":"18","author":"Timmerman","year":"2004","journal-title":"Genes Dev"},{"key":"B78","doi-asserted-by":"publisher","first-page":"1480","DOI":"10.1161\/CIRCRESAHA.115.308077","article-title":"Sequential ligand-dependent notch signaling activation regulates valve primordium formation and morphogenesis","volume":"118","author":"MacGrogan","year":"2016","journal-title":"Circ Res"},{"key":"B79","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1172\/JCI30070","article-title":"An essential role for Notch in neural crest during cardiovascular development and smooth muscle differentiation","volume":"117","author":"High","year":"2007","journal-title":"J Clin Invest"},{"key":"B80","doi-asserted-by":"publisher","first-page":"1826","DOI":"10.1161\/01.CIR.0000160870.93058.DD","article-title":"Essential role of endothelial Notch1 in angiogenesis","volume":"111","author":"Limbourg","year":"2005","journal-title":"Circulation"},{"key":"B81","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1093\/hmg\/10.2.163","article-title":"Familial tetralogy of Fallot caused by mutation in the jagged1 gene","volume":"10","author":"Eldadah","year":"2001","journal-title":"Hum Mol Genet"},{"key":"B82","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/ng0797-243","article-title":"Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1","volume":"16","author":"Li","year":"1997","journal-title":"Nat Genet"},{"key":"B83","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1038\/ng0797-235","article-title":"Mutations in the human Jagged1 gene are responsible for Alagille syndrome","volume":"16","author":"Oda","year":"1997","journal-title":"Nat Genet"},{"key":"B84","doi-asserted-by":"publisher","first-page":"2147","DOI":"10.1084\/jem.20150603","article-title":"Endothelial NOTCH1 is suppressed by circulating lipids and antagonizes inflammation during atherosclerosis","volume":"212","author":"Briot","year":"2015","journal-title":"J Exp Med"},{"key":"B85","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1038\/nm.2021","article-title":"Notch3 signaling promotes the development of pulmonary arterial hypertension","volume":"15","author":"Li","year":"2009","journal-title":"Nat Med"},{"key":"B86","doi-asserted-by":"publisher","first-page":"2733","DOI":"10.1161\/ATVBAHA.113.302062","article-title":"Soluble JAGGED1 inhibits pulmonary hypertension by attenuating notch signaling","volume":"33","author":"Xiao","year":"2013","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B87","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1183\/13993003.00773-2015","article-title":"Notch1 signalling regulates endothelial proliferation and apoptosis in pulmonary arterial hypertension","volume":"48","author":"Dabral","year":"2016","journal-title":"Eur Respir J"},{"key":"B88","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1161\/CIRCRESAHA.118.314496","article-title":"Endothelial Notch1 in pulmonary hypertension","volume":"124","author":"Babicheva","year":"2019","journal-title":"Circ Res"},{"key":"B89","doi-asserted-by":"publisher","first-page":"828","DOI":"10.1016\/j.yjmcc.2009.08.008","article-title":"Notch1 represses osteogenic pathways in aortic valve cells","volume":"47","author":"Nigam","year":"2009","journal-title":"J Mol Cell Cardiol"},{"key":"B90","doi-asserted-by":"publisher","first-page":"e27743","DOI":"10.1371\/journal.pone.0027743","article-title":"Inhibitory role of Notch1 in calcific aortic valve disease","volume":"6","author":"Acharya","year":"2011","journal-title":"PLoS ONE"},{"key":"B91","doi-asserted-by":"publisher","first-page":"1580","DOI":"10.1161\/ATVBAHA.111.227561","article-title":"Diet-induced aortic valve disease in mice haploinsufficient for the Notch pathway effector RBPJK\/CSL","volume":"31","author":"Nus","year":"2011","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B92","doi-asserted-by":"publisher","first-page":"2594","DOI":"10.1002\/dvdy.21246","article-title":"Monitoring Notch1 activity in development: evidence for a feedback regulatory loop","volume":"236","author":"Del Monte","year":"2007","journal-title":"Dev Dyn"},{"key":"B93","doi-asserted-by":"publisher","first-page":"4449","DOI":"10.1242\/dev.084871","article-title":"Endothelial deletion of murine Jag1 leads to valve calcification and congenital heart defects associated with Alagille syndrome","volume":"139","author":"Hofmann","year":"2012","journal-title":"Development"},{"key":"B94","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1083\/jcb.200710067","article-title":"Slug is a direct Notch target required for initiation of cardiac cushion cellularization","volume":"182","author":"Niessen","year":"2008","journal-title":"J Cell Biol"},{"key":"B95","doi-asserted-by":"publisher","first-page":"1986","DOI":"10.1172\/JCI38922","article-title":"Murine Jagged1\/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development","volume":"119","author":"High","year":"2009","journal-title":"J Clin Invest"},{"key":"B96","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1161\/01.RES.0000141136.85194.f0","article-title":"Targeted disruption of hesr2 results in atrioventricular valve anomalies that lead to heart dysfunction","volume":"95","author":"Kokubo","year":"2004","journal-title":"Circ Res"},{"key":"B97","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/j.ydbio.2004.10.025","article-title":"Mouse hesr1 and hesr2 genes are redundantly required to mediate Notch signaling in the developing cardiovascular system","volume":"278","author":"Kokubo","year":"2005","journal-title":"Dev Biol"},{"key":"B98","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1242\/dev.02777","article-title":"Hesr1 and Hesr2 regulate atrioventricular boundary formation in the developing heart through the repression of Tbx2","volume":"134","author":"Kokubo","year":"2007","journal-title":"Development"},{"key":"B99","doi-asserted-by":"publisher","first-page":"4381","DOI":"10.1242\/dev.02607","article-title":"Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors","volume":"133","author":"Rutenberg","year":"2006","journal-title":"Development"},{"key":"B100","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1016\/j.pcad.2020.06.008","article-title":"Embryonic development of bicuspid aortic valves","volume":"63","author":"Soto-Navarrete","year":"2020","journal-title":"Prog Cardiovasc Dis"},{"key":"B101","doi-asserted-by":"publisher","first-page":"1460","DOI":"10.1016\/j.bbrc.2006.05.046","article-title":"Novel missense mutations (p.T596M and p.P1797H) in NOTCH1 in patients with bicuspid aortic valve","volume":"345","author":"Mohamed","year":"2006","journal-title":"Biochem Biophys Res Commun"},{"key":"B102","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.carpath.2006.02.002","article-title":"Calcific bicuspid aortic valve disease in a patient with Cornelia de Lange syndrome: linking altered Notch signaling to aortic valve disease","volume":"15","author":"Oudit","year":"2006","journal-title":"Cardiovasc Pathol"},{"key":"B103","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1016\/j.jtcvs.2007.02.041","article-title":"Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms","volume":"134","author":"McKellar","year":"2007","journal-title":"J Thorac Cardiovasc Surg"},{"key":"B104","doi-asserted-by":"publisher","first-page":"2886","DOI":"10.1093\/hmg\/ddn187","article-title":"NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling","volume":"17","author":"McBride","year":"2008","journal-title":"Hum Mol Genet"},{"key":"B105","doi-asserted-by":"publisher","first-page":"e003075","DOI":"10.1161\/JAHA.115.003075","article-title":"Endothelial Notch1 is required for proper development of the semilunar valves and cardiac outflow tract","volume":"5","author":"Koenig","year":"2016","journal-title":"J Am Heart Assoc"},{"key":"B106","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1161\/CIRCRESAHA.111.245035","article-title":"Nfatc1 coordinates valve endocardial cell lineage development required for heart valve formation","volume":"109","author":"Wu","year":"2011","journal-title":"Circ Res"},{"key":"B107","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1242\/dev.01640","article-title":"Characterization of Nfatc1 regulation identifies an enhancer required for gene expression that is specific to pro-valve endocardial cells in the developing heart","volume":"132","author":"Zhou","year":"2005","journal-title":"Development"},{"key":"B108","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1007\/s11886-018-0968-9","article-title":"Calcific aortic valve disease: a developmental biology perspective","volume":"20","author":"Dutta","year":"2018","journal-title":"Curr Cardiol Rep"},{"key":"B109","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.pcad.2020.06.005","article-title":"Genetics in bicuspid aortic valve disease: where are we?","volume":"63","author":"Bravo-Jaimes","year":"2020","journal-title":"Prog Cardiovasc Dis"},{"key":"B110","doi-asserted-by":"publisher","first-page":"248","DOI":"10.3390\/jcdd2040248","article-title":"Embryonic development of the bicuspid aortic valve","volume":"2","author":"Martin","year":"2015","journal-title":"J Cardiovasc Dev Dis"},{"key":"B111","doi-asserted-by":"publisher","first-page":"2789","DOI":"10.1016\/j.jacc.2009.12.068","article-title":"Bicuspid aortic valve disease","volume":"55","author":"Siu","year":"2010","journal-title":"J Am Coll Cardiol"},{"key":"B112","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.echo.2017.10.008","article-title":"Characteristic morphologies of the bicuspid aortic valve in patients with genetic syndromes","volume":"31","author":"Niaz","year":"2018","journal-title":"J Am Soc Echocardiogr"},{"key":"B113","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1002\/ar.1091470103","article-title":"Abnormal pulmonary and aortic semilunar valves in embryos","volume":"147","author":"Shaner","year":"1963","journal-title":"Anat Rec"},{"key":"B114","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1007\/BF02190547","article-title":"Coronary artery anomalies and bicuspid aortic valves in the Syrian hamster","volume":"86","author":"Sans-Coma","year":"1991","journal-title":"Basic Res Cardiol"},{"key":"B115","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/0167-5273(92)90021-T","article-title":"Bicuspid aortic and pulmonary valves in the Syrian hamster","volume":"34","author":"Sans-Coma","year":"1992","journal-title":"Int J Cardiol"},{"key":"B116","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1002\/(SICI)1097-0185(199604)244:4<490::AID-AR7>3.0.CO;2-Z","article-title":"Fusion of valve cushions as a key factor in the formation of congenital bicuspid aortic valves in Syrian hamsters","volume":"244","author":"Sans-Coma","year":"1996","journal-title":"Anat Rec"},{"key":"B117","doi-asserted-by":"publisher","first-page":"2312","DOI":"10.1016\/j.jacc.2009.07.044","article-title":"Bicuspid aortic valves with different spatial orientations of the leaflets are distinct etiological entities","volume":"54","author":"Fernandez","year":"2009","journal-title":"J Am Coll Cardiol"},{"key":"B118","doi-asserted-by":"publisher","first-page":"2345","DOI":"10.1161\/01.CIR.101.20.2345","article-title":"Abnormal aortic valve development in mice lacking endothelial nitric oxide synthase","volume":"101","author":"Lee","year":"2000","journal-title":"Circulation"},{"key":"B119","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.1242\/dev.048926","article-title":"HB-EGF function in cardiac valve development requires interaction with heparan sulfate proteoglycans","volume":"137","author":"Iwamoto","year":"2010","journal-title":"Development"},{"key":"B120","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.yjmcc.2019.03.013","article-title":"Chronic inflammation: A key role in degeneration of bicuspid aortic valve","volume":"130","author":"Manno","year":"2019","journal-title":"J Mol Cell Cardiol"},{"key":"B121","doi-asserted-by":"publisher","first-page":"H1302","DOI":"10.1152\/ajpheart.00392.2013","article-title":"Aortic valve sclerosis in mice deficient in endothelial nitric oxide synthase","volume":"306","author":"El Accaoui","year":"2014","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B122","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.jacc.2015.05.066","article-title":"Calcification in aortic stenosis: the skeleton key","volume":"66","author":"Pawade","year":"2015","journal-title":"J Am Coll Cardiol"},{"key":"B123","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1001\/archinte.165.8.858","article-title":"Angiotensin-converting enzyme inhibitors and change in aortic valve calcium","volume":"165","author":"O'Brien","year":"2005","journal-title":"Arch Intern Med"},{"key":"B124","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1159\/000350896","article-title":"Angiotensin receptor blockers are associated with reduced fibrosis and interleukin-6 expression in calcific aortic valve disease","volume":"81","author":"Cote","year":"2014","journal-title":"Pathobiology"},{"key":"B125","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.molmed.2012.12.008","article-title":"Vitamin K-dependent carboxylation of matrix Gla-protein: a crucial switch to control ectopic mineralization","volume":"19","author":"Schurgers","year":"2013","journal-title":"Trends Mol Med"},{"key":"B126","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1093\/cvr\/cvz210","article-title":"Therapeutic inhibition of microRNA-34a ameliorates aortic valve calcification via modulation of Notch1-Runx2 signaling","volume":"116","author":"Toshima","year":"2019","journal-title":"Cardiovasc Res"},{"key":"B127","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.jjcc.2017.11.007","article-title":"Mechanisms of aortic stenosis","volume":"71","author":"Akahori","year":"2018","journal-title":"J Cardiol"},{"key":"B128","doi-asserted-by":"publisher","first-page":"e13027","DOI":"10.1111\/eci.13027","article-title":"Variants in cardiac GATA genes associated with bicuspid aortic valve","volume":"48","author":"Alonso-Montes","year":"2018","journal-title":"Eur J Clin Invest"},{"key":"B129","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1161\/CIRCULATIONAHA.117.029506","article-title":"GATA6 regulates aortic valve remodeling, and its haploinsufficiency leads to right-left type bicuspid aortic valve","volume":"138","author":"Gharibeh","year":"2018","journal-title":"Circulation"},{"key":"B130","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1016\/j.amjcard.2017.11.012","article-title":"GATA4 Loss-of-Function mutation and the congenitally bicuspid aortic valve","volume":"121","author":"Li","year":"2018","journal-title":"Am J Cardiol"},{"key":"B131","doi-asserted-by":"publisher","first-page":"2876","DOI":"10.1172\/JCI44555","article-title":"Loss of Gata5 in mice leads to bicuspid aortic valve","volume":"121","author":"Laforest","year":"2011","journal-title":"J Clin Invest"},{"key":"B132","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1038\/pr.2014.67","article-title":"Rare GATA5 sequence variants identified in individuals with bicuspid aortic valve","volume":"76","author":"Bonachea","year":"2014","journal-title":"Pediatr Res"},{"key":"B133","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.yjmcc.2017.11.009","article-title":"Different Notch signaling in cells from calcified bicuspid and tricuspid aortic valves","volume":"114","author":"Kostina","year":"2018","journal-title":"J Mol Cell Cardiol"},{"key":"B134","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.yjmcc.2013.04.001","article-title":"Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease","volume":"60","author":"Bosse","year":"2013","journal-title":"J Mol Cell Cardiol"},{"key":"B135","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3390\/jcdd2010017","article-title":"Evidence of Aortopathy in Mice with Haploinsufficiency of Notch1 in Nos3-Null Background","volume":"2","author":"Koenig","year":"2015","journal-title":"J Cardiovasc Dev Dis"},{"key":"B136","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.yjmcc.2015.04.006","article-title":"NOTCH1 regulates matrix gla protein and calcification gene networks in human valve endothelium","volume":"84","author":"White","year":"2015","journal-title":"J Mol Cell Cardiol"},{"key":"B137","doi-asserted-by":"publisher","first-page":"eabe3706","DOI":"10.1126\/sciadv.abe3706","article-title":"Nitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling","volume":"7","author":"Majumdar","year":"2021","journal-title":"Sci Adv"},{"key":"B138","doi-asserted-by":"publisher","first-page":"6917907","DOI":"10.1155\/2017\/6917907","article-title":"NOTCH1 mutations in aortic stenosis: association with Osteoprotegerin\/RANK\/RANKL","volume":"2017","author":"Irtyuga","year":"2017","journal-title":"Biomed Res Int"},{"key":"B139","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1016\/j.cell.2015.02.035","article-title":"Human disease modeling reveals integrated transcriptional and epigenetic mechanisms of NOTCH1 haploinsufficiency","volume":"160","author":"Theodoris","year":"2015","journal-title":"Cell"},{"key":"B140","doi-asserted-by":"publisher","first-page":"1683","DOI":"10.1172\/JCI90338","article-title":"Long telomeres protect against age-dependent cardiac disease caused by NOTCH1 haploinsufficiency","volume":"127","author":"Theodoris","year":"2017","journal-title":"J Clin Invest"},{"key":"B141","doi-asserted-by":"publisher","first-page":"eabd0724","DOI":"10.1126\/science.abd0724","article-title":"Network-based screen in iPSC-derived cells reveals therapeutic candidate for heart valve disease","volume":"371","author":"Theodoris","year":"2021","journal-title":"Science"}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2021.682298\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T00:19:58Z","timestamp":1624321198000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2021.682298\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,22]]},"references-count":141,"alternative-id":["10.3389\/fcvm.2021.682298"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2021.682298","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,22]]},"article-number":"682298"}}