Key result
Nos3 mutation in mice altered neural crest and second heart field cell deposition, causing incomplete separation of the parietal outflow tract cushion and bicuspid aortic valve formation.
The study demonstrates that abnormal distribution of neural crest and second heart field cells due to Nos3 mutation leads to the formation of right-non-type bicuspid aortic valves.
Provides mechanistic insight into BAV in models; leaves open translation to human valvulogenesis or therapies.
The bicuspid aortic valve (BAV), a valve with two instead of three aortic leaflets, belongs to the most prevalent congenital heart diseases in the world, occurring in 0.5-2% of the general population. We aimed to understand how changes in early cellular contributions result in BAV formation and impact cardiovascular outflow tract development. Detailed 3D reconstructions, immunohistochemistry and morphometrics determined that, during valvulogenesis, the non-coronary leaflet separates from the parietal outflow tract cushion instead of originating from an intercalated cushion. Nos3−/− mice develop a BAV without a raphe as a result of incomplete separation of the parietal outflow tract cushion into the right and non-coronary leaflet. Genetic lineage tracing of endothelial, second heart field and neural crest cells revealed altered deposition of neural crest cells and second heart field cells within the parietal outflow tract cushion of Nos3−/− embryos. The abnormal cell lineage distributions also affected the positioning of the aortic and pulmonary valves at the orifice level. The results demonstrate that the development of the right and non-coronary leaflets are closely related. A small deviation in the distribution of neural crest and second heart field populations affects normal valve formation and results in the predominant right-non-type BAV in Nos3−/− mice.
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Peterson et al. (2018) studied Bicuspid aortic valve. Nos3 mutation was evaluated on Valve formation and cellular lineage distribution. Nos3 mutation in mice altered neural crest and second heart field cell deposition, causing incomplete separation of the parietal outflow tract cushion and bicuspid aortic valve formation.
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