Abnormal aortic valve development in mice lacking endothelial nitric oxidesynthase

Background-Endothelium-derived nitric oxide (NO) is produced by an oxidativ e reaction catalyzed by endothelial NO synthase (eNOS). NO plays a crucial role in controlling cell growth and apoptosis, as well as having well-chara cterized vasodilator and antithrombotic actions. More recently, endothelium -derived NO was shown to be involved in postdevelopmental vascular remodeli ng and angiogenesis, as well as in the formation of limb vasculature during embryogenesis, Therefore, we investigated the role of endothelium-derived NO during cardiovascular development using mice deficient in eNOS. Methods and Results-We examined the hearts of 12 mature eNOS-deficient and 26 mature wild-type mice. Five of the mature eNOS-deficient mice had a bicu spid aortic valve; none of the 26 wild-type animals exhibited identifiable valvular or cardiac abnormalities. Immunohistochemical analysis revealed pr ominent eNOS expression localized to the endothelium lining the valve cusps of the aorta in mature wild-type mice; expression was localized to the myo cardium and endothelial cell monolayer lining the valve leaflets in the dev eloping embryo. Conclusions-These results show a strong association between eNOS deficiency and the presence of a bicuspid aortic valve; they provide the first molecu lar insight into one of the most common types of congenital cardiac abnorma lity.