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

Abstract

Clinical Perspective on p 2225In healthy individuals, plasma ADMA concentrations are maintained at ≈0.5μmol/L through a combination of enzymatic breakdown and renal excretion that account for ≈80% and ≈20% of clearance, respectively.10 Asymmetrical methylarginines are metabolized by the action of dimethylarginine 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) to investigate the significance of endothelial ADMA in cardiovascular homeostasis. Methods and Results-DDAH1 deletion in the DDAH1En−/− 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 DDAH1En−/− 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.

Cardiomyocyte dimethylarginine dimethylaminohydrolase-1 (DDAH1) plays an important role in attenuating ventricular hypertrophy and dysfunction

“…However, chronic accumulation of ADMA in global DDAH1 KO causes reduced vascular NO production, moderate hypertension, and diminished acetylcholine-induced vasodilatation [16, 23]. ADMA accumulation in global DDAH1 KO mice or endothelial specific DDAH1 KO mice also results in reduced angiogenesis and impaired vascular injury repair capacity [11, 39, 40]. Conversely, over-expression of DDAH1 results in decreases of plasma and tissue ADMA levels, which was associated decrease of systemic blood pressure [10], increase of insulin sensitivity [35], increase of angiogenesis [19], and reduced high fat diet induced atherosclerosis [38].…”

Effect of asymmetric dimethylarginine (ADMA) on heart failure development

“…Thus, DDAH1 gene deficiency causes increases of plasma and tissue ADMA and L-NMMA, which is associated with reduced NO production, moderate hypertension, and endothelial dysfunction (43,44,63). DDAH1 gene deficiency also limits angiogenesis and impairs vascular injury repair (30,113,115). Conversely, over-expression of DDAH1 results in decreases of plasma and tissue ADMA levels, which was associated decrease of systemic blood pressure (28), increase of insulin sensitivity (94), increase of angiogenesis (53,113,115), reduced high fat diet induced atherosclerosis (52,108) and graft coronary artery disease (98).…”

“…Using the Tie-2 Cre system, we found that endothelial specific DDAH1 gene deletion caused significant decreases of DDAH1 in vascular tissues, increased tissue and plasma ADMA, reduced acetylcholine induced NO production and vessel dilatation, and resulted in systemic hypertension (43,44), abnormal angiogenesis, and impaired endothelial injury repair (113,115). However, using a similar Tie-2 Cre system, a new endothelial specific DDAH1 strain was shown to have no major effect on systemic ADMA content (30), but significantly attenuated angiogenesis (30). While endothelial specific DDAH1 gene deletion using Tie-2 Cre system attenuated endothelial injury repairs and angiogenesis in both mouse strains, the effect of endothelial DDAH1 gene deletion on systemic blood ADMA was different in these mouse strains.…”

DDAH1 regulates apoptosis and angiogenesis in human fetal pulmonary microvascular endothelial cells

“…; Dowsett et al. ). DDAH1/ADMA/NOS pathway regulation of caspase‐3 mediated apoptosis has been described (Wang et al.…”

“…In a variety of vascular diseases, decreased DDAH expression/activity is associated with endothelial dysfunction mediated by increased levels of ADMA causing inhibition of eNOS (Pope et al 2009a). Endothelial DDAH1-specific knockout mice have impaired angiogenesis (Zhang et al 2013;Dowsett et al 2015). DDAH1/ADMA/NOS pathway regulation of caspase-3 mediated apoptosis has been described (Wang et al 2016;Hou et al 2018;Liu et al 2018), and DDAH1 upregulation has been associated with tumor regression in a xenograft mouse model (Yung et al 2016).…”