Vascular Endothelial-Specific Dimethylarginine Dimethylaminohydrolase-1–Deficient Mice Reveal That Vascular Endothelium Plays an Important Role in Removing Asymmetric Dimethylarginine

Background— Asymmetrical methylarginines inhibit NO synthase activity and thereby decrease NO production. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) degrades asymmetrical methylarginines. We previously demonstrated that in the heart DDAH1 is predominantly expressed in vascular endothelial cells. Because an earlier study showed that mice with global DDAH1 deficiency experienced embryonic lethality, we speculated that a mouse strain with selective vascular endothelial DDAH1 deficiency (endo-DDAH1−/−) would largely abolish tissue DDAH1 expression in many tissues but possibly avoid embryonic lethality. Methods and Results— By using the LoxP/Cre approach, we generated the endo-DDAH1−/− mice. The endo-DDAH1−/− mice had no apparent defect in growth or development compared with wild-type littermates. DDAH1 expression was greatly reduced in kidney, lung, brain, and liver, indicating that in these organs DDAH1 is distributed mainly in vascular endothelial cells. The endo-DDAH1−/− mice showed a significant in...