Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract
BackgroundCongenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar valves account for >50% of these cases predominantly because of a bicuspid aortic valve, which has an estimated prevalence o...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2016-04-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.115.003075 |
| _version_ | 1818315206475907072 |
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| author | Sara N. Koenig Kevin Bosse Uddalak Majumdar Elizabeth M. Bonachea Freddy Radtke Vidu Garg |
| author_facet | Sara N. Koenig Kevin Bosse Uddalak Majumdar Elizabeth M. Bonachea Freddy Radtke Vidu Garg |
| author_sort | Sara N. Koenig |
| collection | DOAJ |
| description | BackgroundCongenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar valves account for >50% of these cases predominantly because of a bicuspid aortic valve, which has an estimated prevalence of 1% in the population. We previously reported that mutations in NOTCH1 were a cause of bicuspid aortic valve in nonsyndromic autosomal‐dominant human pedigrees. Subsequently, we described a highly penetrant mouse model of aortic valve disease, consisting of a bicuspid aortic valve with thickened cusps and associated stenosis and regurgitation, in Notch1‐haploinsufficient adult mice backcrossed into a Nos3‐null background. Methods and ResultsHere, we described the congenital cardiac abnormalities in Notch1+/−;Nos3−/− embryos that led to ≈65% lethality by postnatal day 10. Although expected Mendelian ratios of Notch1+/−;Nos3−/− embryos were found at embryonic day 18.5, histological examination revealed thickened, malformed semilunar valve leaflets accompanied by additional anomalies of the cardiac outflow tract including ventricular septal defects and overriding aorta. The aortic valve leaflets of Notch1+/−;Nos3−/− embryos at embryonic day 15.5 were significantly thicker than controls, consistent with a defect in remodeling of the semilunar valve cushions. In addition, we generated mice haploinsufficient for Notch1 specifically in endothelial and endothelial‐derived cells in a Nos3‐null background and found that Notch1fl/+;Tie2‐Cre+/−;Nos3−/− mice recapitulate the congenital cardiac phenotype of Notch1+/−;Nos3−/− embryos. ConclusionsOur data demonstrate the role of endothelial Notch1 in the proper development of the semilunar valves and cardiac outflow tract. |
| first_indexed | 2024-12-13T09:01:51Z |
| format | Article |
| id | doaj.art-89612898f1ec4105b7cbe20f001c4617 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-13T09:01:51Z |
| publishDate | 2016-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-89612898f1ec4105b7cbe20f001c46172022-12-21T23:53:09ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802016-04-015410.1161/JAHA.115.003075Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow TractSara N. Koenig0Kevin Bosse1Uddalak Majumdar2Elizabeth M. Bonachea3Freddy Radtke4Vidu Garg5Center for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Children's Hospital, Columbus, OHCenter for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Children's Hospital, Columbus, OHCenter for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Children's Hospital, Columbus, OHDepartment of Pediatrics, The Ohio State University, Columbus, OHEcole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research, Lausanne, SwitzerlandCenter for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Children's Hospital, Columbus, OHBackgroundCongenital heart disease is the most common type of birth defect, affecting ≈2% of the population. Malformations involving the cardiac outflow tract and semilunar valves account for >50% of these cases predominantly because of a bicuspid aortic valve, which has an estimated prevalence of 1% in the population. We previously reported that mutations in NOTCH1 were a cause of bicuspid aortic valve in nonsyndromic autosomal‐dominant human pedigrees. Subsequently, we described a highly penetrant mouse model of aortic valve disease, consisting of a bicuspid aortic valve with thickened cusps and associated stenosis and regurgitation, in Notch1‐haploinsufficient adult mice backcrossed into a Nos3‐null background. Methods and ResultsHere, we described the congenital cardiac abnormalities in Notch1+/−;Nos3−/− embryos that led to ≈65% lethality by postnatal day 10. Although expected Mendelian ratios of Notch1+/−;Nos3−/− embryos were found at embryonic day 18.5, histological examination revealed thickened, malformed semilunar valve leaflets accompanied by additional anomalies of the cardiac outflow tract including ventricular septal defects and overriding aorta. The aortic valve leaflets of Notch1+/−;Nos3−/− embryos at embryonic day 15.5 were significantly thicker than controls, consistent with a defect in remodeling of the semilunar valve cushions. In addition, we generated mice haploinsufficient for Notch1 specifically in endothelial and endothelial‐derived cells in a Nos3‐null background and found that Notch1fl/+;Tie2‐Cre+/−;Nos3−/− mice recapitulate the congenital cardiac phenotype of Notch1+/−;Nos3−/− embryos. ConclusionsOur data demonstrate the role of endothelial Notch1 in the proper development of the semilunar valves and cardiac outflow tract.https://www.ahajournals.org/doi/10.1161/JAHA.115.003075bicuspid aortic valvecardiovascular geneticscongenital heart defectconotruncal heart defectsNotch1 signaling |
| spellingShingle | Sara N. Koenig Kevin Bosse Uddalak Majumdar Elizabeth M. Bonachea Freddy Radtke Vidu Garg Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease bicuspid aortic valve cardiovascular genetics congenital heart defect conotruncal heart defects Notch1 signaling |
| title | Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract |
| title_full | Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract |
| title_fullStr | Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract |
| title_full_unstemmed | Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract |
| title_short | Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract |
| title_sort | endothelial notch1 is required for proper development of the semilunar valves and cardiac outflow tract |
| topic | bicuspid aortic valve cardiovascular genetics congenital heart defect conotruncal heart defects Notch1 signaling |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.115.003075 |
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