Abstract 9782: Disruption of Notch1 and Gata5 in Mice Results in Clinically Relevant Aortic Valve Disease

Abstract

Congenital malformations of the aortic valve are the most common type of congenital heart defect, but the underlying mechanisms of congenital aortic valve disease (AVD) remain poorly understood. NOTCH1 mutations are associated with AVD, and we previously reported that Notch1;Nos3 mutant mice display AVD. However, this mouse model has limitations since ~65% mutant mice suffer neonatal lethality. GATA5 is also implicated in human AVD, and Gata5 -/- mice display bicuspid aortic valve, with an associated reduction in Notch signaling. We hypothesized that interaction of Notch1 and Gata5 was critical for aortic valve morphogenesis, and generated novel murine models by intercrossing Notch1 and Gata5 heterozygote mice. We characterized the cardiac phenotype in mice that are heterozygous for Notch1 and Gata5 ( Notch1 +/- ;Gata5 +/- ) and also those that are heterozygous for Notch1 and null for Gata5 ( Notch1 +/- ;Gata5 -/- ). While normal Mendelian ratios were present at 6 weeks and 4 months of age, echocardiography demonstrated an increased incidence of aortic stenosis/regurgitation in Notch1 +/- ;Gata5 +/- mice (52%: 11/21) and Notch1 +/- ;Gata5 -/- mice (86%: 6/7). Histological examination revealed thickened, dysmorphic aortic valve cusps and left ventricular hypertrophy in Notch1 +/- ;Gata5 +/- and Notch1 +/- ;Gata5 -/- mice compared to wild-type, Notch1 +/- , Gata5 +/- , and Gata5 -/- mice. In addition, 1 year old Notch1 +/- ;Gata5 +/- mice displayed 100% incidence of aortic valve stenosis/regurgitation with thickened valve cusps. At postnatal day 10, the aortic valve cusps of Notch1 +/- ;Gata5 +/- and Notch1 +/- ;Gata5 -/- mice were significantly larger than controls consistent with a neonatal phenotype. Interestingly, Notch1 +/- ;Gata5 -/- mice displayed significantly thickened aortic valve cusps compared to Notch1 +/- ;Gata5 +/- mice. Further examination at embryonic day 18.5 demonstrated thickened, malformed aortic valves in Notch1;Gata5 mutant embryos. In conclusion, our findings demonstrate a novel genetic interaction of Notch1 and Gata5 necessary for the proper remodeling of aortic valves. Our new mouse models display highly penetrant congenital AVD without lethality, allowing for studying disease progression to identify novel therapeutic targets.