Abstract 18574: Examination of a Highly Penetrant Mouse Model of Bicuspid Aortic Valve Demonstrates that Endothelial Notch1 is Required for Proper Morphogenesis of the Aortic Valve
Bicuspid aortic valve (BAV) is the most common type of cardiac malformation with an estimated prevalence of 1-2% in the population. BAV results in significant morbidity as it is one of the leading causes of valve stenosis and regurgitation in adults. We previously reported that mutations in the signaling and transcriptional regulator, NOTCH1, were a cause of BAV in non-syndromic autosomal-dominant human pedigrees. The Notch signaling pathway is critical for multiple cell differentiation processes, and Notch1 is expressed in the developing and adult aortic valve. Recently, we have generated a new highly penetrant mouse model of aortic valve malformations using Notch1 haploinsufficient mice that are backcrossed in a Nos3-null background. Notch1 and Nos3 compound mutant adult mice (Notch1+/-;Nos3-/-) display a nearly 100% incidence of BAV. The aortic valves of adult mutant mice are thickened and have associated stenosis and regurgitation. We have also found that by postnatal day 10, compound mutant mice suffer ~50% lethality compared to NOS3-/- littermates. Here, we have examined Notch1+/-;Nos3-/- embryos at serial timepoints to elucidate the mechanisms underlying BAV. Examination at embryonic day 18.5 (E18.5) demonstrated normal Mendelian ratios and histologic examination revealed thickened, malformed valve leaflets accompanied by other outflow tract abnormalities in NOS3-/-;Notch1-/+ mice, likely contributing to the neonatal lethality. Further investigation at E13.5 and E15.5 indicated that the NOS3-/-;Notch1-/+ aortic valve leaflets were significantly thicker than controls, suggesting that outflow tract cushion formation and early remodeling may be affected. In addition, we have generated mice are null for Nos3 and haploinsufficient for Notch1 in endothelial-derived cells using mice harboring a Notch1-floxed allele and Tie2-Cre mice. Our preliminary results indicate that NOS3-/-;Notch1fl/+;Tie2Cre+ mice recapitulate the NOS3-/-;Notch1-/+ cardiac phenotype and suggest that endothelial Notch1 is required for proper development of the aortic valve. Overall our data indicate that loss of endothelial Notch1 results in abnormal remodeling of the outflow tract cushions and contributes to BAV.
- Aortic valve
- Biology, developmental
- Congenital heart disease
- Cardiovascular development
- Valvular heart disease
- © 2013 by American Heart Association, Inc.