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

Abstract

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 increase of asymmetric dimethylarginine concentration in plasma (1.41 μmol/L in the endo-DDAH1 −/− versus 0.69 μmol/L in the control mice), kidney, lung, and liver, which was associated with significantly increased systolic blood pressure (132 mm Hg versus 113 mm Hg in wild-type). The endo-DDAH1 −/− mice also exhibited significantly attenuated acetylcholine-induced NO production and vessel relaxation in isolated aortic rings. Conclusions— Our study demonstrates that DDAH1 is highly expressed in vascular endothelium and that endothelial DDAH1 plays an important role in regulating blood pressure. In the context that asymmetric methylarginines are broadly produced by many type of cells, the strong DDAH1 expression in vascular endothelium demonstrates for the first time that vascular endothelium can be an important site to actively dispose of toxic biochemical molecules produced by other types of cells.