Bicuspid aortic valve formation: Nos3 mutation leads to abnormal lineage patterning of neural crest cells and the second heart field

Joshua C Peterson,Qingping Feng,Adriana C Gittenberger-De Groot,Marco C Deruiter,Monique R M Jongbloed,Marie-José T H Goumans,Lambertus J Wisse,J Conny Vanmunsteren,Mary Chughtai

doi:10.1242/dmm.034637

Joshua C Peterson, Qingping Feng + Show 7 more

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https://doi.org/10.1242/dmm.034637

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Abstract

ABSTRACTThe 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.

Highlights

The tricuspid aortic valve (TAV) has a crucial role in maintaining unidirectional blood flow from the left ventricle into the systemic circulation
We examined the contributions of neural crest, endothelial and SHF lineages in aortic valve development of wildtype and Nos3−/− mouse embryos to identify novel congenital aberrations involved in the formation of a bicuspid aortic valve (BAV)
Nos3−/− embryos develop BAV due to defects in endothelial-linked separation of the parietal cushion into the NC and right coronary (RC) aortic leaflet accompanied by a different pattern of disposition of embryonic cell lineages

Summary

Introduction

The tricuspid aortic valve (TAV) has a crucial role in maintaining unidirectional blood flow from the left ventricle into the systemic circulation. Received 22 March 2018; Accepted 5 September 2018 aneurysm development (Ward, 2000; Verma and Siu, 2014; Sievers et al, 2015; Merkx et al, 2017). A BAV is currently accepted as a congenital anomaly with a high incidence, occurring in 0.5-2% of the Western population (Roberts, 1970; Ward, 2000; Hoffman and Kaplan, 2002). BAV formation is generally considered to be an abnormal fusion of aortic leaflets occurring during embryonic development (Fernández et al, 2009; Théron et al, 2015; Odelin et al, 2017). Leaflet fusion might be a valid mechanistic explanation, there are currently no unequivocal data supporting this mechanism in BAV mouse models

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