Abstract
Nitric oxide synthase-3 (NOS3) has recently been shown to promote endothelial-to-mesenchymal transition (EndMT) in the developing atrioventricular (AV) canal. The present study was aimed to investigate the role of NOS3 in embryonic development of AV valves. We hypothesized that NOS3 promotes embryonic development of AV valves via EndMT. To test this hypothesis, morphological and functional analysis of AV valves were performed in wild-type (WT) and NOS3−/− mice at postnatal day 0. Our data show that the overall size and length of mitral and tricuspid valves were decreased in NOS3−/− compared with WT mice. Echocardiographic assessment showed significant regurgitation of mitral and tricuspid valves during systole in NOS3−/− mice. These phenotypes were all rescued by cardiac specific NOS3 overexpression. To assess EndMT, immunostaining of Snail1 was performed in the embryonic heart. Both total mesenchymal and Snail1+ cells in the AV cushion were decreased in NOS3−/− compared with WT mice at E10.5 and E12.5, which was completely restored by cardiac specific NOS3 overexpression. In cultured embryonic hearts, NOS3 promoted transforming growth factor (TGFβ), bone morphogenetic protein (BMP2) and Snail1expression through cGMP. Furthermore, mesenchymal cell formation and migration from cultured AV cushion explants were decreased in the NOS3−/− compared with WT mice. We conclude that NOS3 promotes AV valve formation during embryonic heart development and deficiency in NOS3 results in AV valve insufficiency.
Highlights
Valvular heart disease is a significant health problem and contributes to more than 44,000 deaths in United States annually [1]
Quantitative analysis of mitral and tricuspid valves show that the size and length of the proximal and distal leaflets were significantly smaller in the NOS32/2 compared with Nitric oxide synthase-3 (NOS3)+/+ hearts (P,0.05, Figure 1E–F, K–L, S1F, S2F)
Our data showed that there was no significant difference in cell density in mitral and tricuspid valves among all groups at P0 (Figure S1G and S2G)
Summary
Valvular heart disease is a significant health problem and contributes to more than 44,000 deaths in United States annually [1]. The causes of valvular heart disease include congenital malformation and rheumatic disease which is secondary to bacterial infection. Congenital valve disease affects about 2% of the general population [2,3]. The disease may manifest as valvular stenosis, an obstruction of outflow, or as regurgitation, a defective closure resulting in backward flow. Congenital valve malformations tend to cluster in families among both close and distant relatives, suggesting a genetic component of this disease [4,5]. Molecular mechanisms responsible for congenital valve disease are still not fully understood
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