NOing the heart: role of nitric oxide synthase-3 in heart development.

Congenital heart disease is the most common birth defect in humans. Identifying factors that are critical to embryonic heart development could further our understanding of the disease and lead to new strategies of its prevention and treatment. Nitric oxide synthase-3 (NOS3) or endothelial nitric oxide synthase (eNOS) is known for many important biological functions including vasodilation, vascular homeostasis and angiogenesis. Over the past decade, studies from our lab and others have shown that NOS3 is required during heart development. More specifically, deficiency in NOS3 results in congenital septal defects, cardiac hypertrophy and postnatal heart failure. In addition, NOS3 is pivotal to the morphogenesis of major coronary arteries and myocardial capillary development. Interestingly, these effects of NOS3 are mediated through induction of transcription and growth factors that are crucial in the formation of coronary arteries. Finally, deficiency in NOS3 results in high incidences of bicuspid aortic valves, a disease in humans that often leads to complications with age including aortic valve stenosis or regurgitation, endocarditis, aortic aneurysm formation, and aortic dissection. In summary, these data suggest NOS3 plays a critical role in embryonic heart development and morphogenesis of coronary arteries and aortic valves.