Endothelial Notch1 Is Required for Proper Development of the Semilunar Valves and Cardiac Outflow Tract.
Congenital 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.



Here, 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 Notch1(fl/+);Tie2-Cre(+/-);Nos3(-/-) mice recapitulate the congenital cardiac phenotype of Notch1(+/-);Nos3(-/-) embryos.



Our data demonstrate the role of endothelial Notch1 in the proper development of the semilunar valves and cardiac outflow tract.
Center for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Children's Hospital, Columbus, OH.
Sara N
SN
Koenig
Center for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Children's Hospital, Columbus, OH.
Kevin
K
Bosse
Center for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Children's Hospital, Columbus, OH.
Uddalak
U
Majumdar
Department of Pediatrics, The Ohio State University, Columbus, OH.
Elizabeth M
EM
Bonachea
Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland.
Freddy
F
Radtke
Center for Cardiovascular and Pulmonary Research and The Heart Center, Nationwide Children's Hospital, Columbus, OH Department of Pediatrics, The Ohio State University, Columbus, OH Department of Molecular Genetics, The Ohio State University, Columbus, OH vidu.garg@nationwidechildrens.org.
Vidu
V
Garg
D000818:Animals; D001021:Aortic Valve / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D000082882:Bicuspid Aortic Valve Disease; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D006349:Heart Valve Diseases / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D006351:Heart Valves / Q000196:embryology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism
C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D004247:DNA
Notch1 signaling; bicuspid aortic valve; cardiovascular genetics; congenital heart defect; conotruncal heart defects