Abnormal aortic valve development in mice lacking endothelial nitric oxide synthase.
BACKGROUND
Endothelium-derived nitric oxide (NO) is produced by an oxidative reaction catalyzed by endothelial NO synthase (eNOS). NO plays a crucial role in controlling cell growth and apoptosis, as well as having well-characterized vasodilator and antithrombotic actions. More recently, endothelium-derived NO was shown to be involved in postdevelopmental vascular remodeling 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.


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 bicuspid aortic valve; none of the 26 wild-type animals exhibited identifiable valvular or cardiac abnormalities. Immunohistochemical analysis revealed prominent eNOS expression localized to the endothelium lining the valve cusps of the aorta in mature wild-type mice; expression was localized to the myocardium and endothelial cell monolayer lining the valve leaflets in the developing embryo.


CONCLUSIONS
These results show a strong association between eNOS deficiency and the presence of a bicuspid aortic valve; they provide the first molecular insight into one of the most common types of congenital cardiac abnormality.
Lee
T C
TC
Division of Cardiology, Terrence Donnelly Heart Center, St Michael's Hospital, University of Toronto, Ontario, Canada.
Zhao
Y D
YD
Courtman
D W
DW
Stewart
D J
DJ
D000818:Animals; D001021:Aortic Valve / Q000002:abnormalities* / Q000201:enzymology / Q000473:pathology; D004622:Embryo, Mammalian / Q000378:metabolism; D004730:Endothelium, Vascular / Q000196:embryology / Q000473:pathology; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D012016:Reference Values; D014018:Tissue Distribution
D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse