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Endothelial Dimethylarginine Dimethylaminohydrolase 1 Is an Important Regulator of Angiogenesis but Does Not Regulate Vascular Reactivity or Hemodynamic Homeostasis

2015; Lippincott Williams & Wilkins; Volume: 131; Issue: 25 Linguagem: Inglês

10.1161/circulationaha.114.015064

1524-4539

Laura Dowsett, Sophie Piper, Anna Slaviero, Neil Dufton, Zhen Wang, Olga Boruc, Matthew Delahaye, Lucy Colman, Eliza Kalk, James Tomlinson, Graeme M. Birdsey, Anna M. Randi, James Leiper,

Eicosanoids and Hypertension Pharmacology

Background— Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthesis and a risk factor for cardiovascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) enzymes are responsible for ADMA breakdown. It has been reported that endothelial DDAH1 accounts for the majority of ADMA metabolism. However, we and others have shown strong DDAH1 expression in a range of nonendothelial cell types, suggesting that the endothelium is not the only site of metabolism. We have developed a new endothelium-specific DDAH1 knockout mouse (DDAH1 En−/− ) to investigate the significance of endothelial ADMA in cardiovascular homeostasis. Methods and Results— DDAH1 deletion in the DDAH1 En−/− mouse was mediated by Tie-2 driven Cre expression. DDAH1 deletion was confirmed through immunocytochemistry, whereas Western blotting showed that DDAH1 remained in the kidney and liver, confirming expression in nonendothelial cells. Plasma ADMA was unchanged in DDAH1 En−/− mice, and cultured aortas released amounts of ADMA to similar to controls. Consistent with these observations, vasoreactivity ex vivo and hemodynamics in vivo were unaltered in DDAH1 En−/− mice. In contrast, we observed significantly impaired angiogenic responses both ex vivo and in vivo. Conclusions— We demonstrate that endothelial DDAH1 is not a critical determinant of plasma ADMA, vascular reactivity, or hemodynamic homeostasis. DDAH1 is widely expressed in a range of vascular and nonvascular cell types; therefore, the additive effect of DDAH1 expression in multiple organ systems determines plasma ADMA concentrations. Endothelial deletion of DDAH1 profoundly impairs the angiogenic capacity of endothelial cells, indicating that intracellular ADMA is a critical determinant of endothelial cell response.