Abstract
AimArgininosuccinate synthetase (ASS) is essential for recycling L-citrulline, the by-product of NO synthase (NOS), to the NOS substrate L-arginine. Here, we assessed whether disturbed arginine resynthesis modulates endothelium-dependent vasodilatation in normal and diabetic male mice.Methods and ResultsEndothelium-selective Ass-deficient mice (Assfl/fl/Tie2Cretg/− = Ass-KOTie2) were generated by crossing Assfl/fl mice ( = control) with Tie2Cre mice. Gene ablation in endothelial cells was confirmed by immunohistochemistry. Blood pressure (MAP) was recorded in 34-week-old male mice. Vasomotor responses were studied in isolated saphenous arteries of 12- and 34-week-old Ass-KOTie2 and control animals. At the age of 10 weeks, diabetes was induced in control and Ass-KOTie2 mice by streptozotocin injections. Vasomotor responses of diabetic animals were studied 10 weeks later. MAP was similar in control and Ass-KOTie2 mice. Depletion of circulating L-arginine by arginase 1 infusion or inhibition of NOS activity with L-NAME resulted in an increased MAP (10 and 30 mmHg, respectively) in control and Ass-KOTie2 mice. Optimal arterial diameter, contractile responses to phenylephrine, and relaxing responses to acetylcholine and sodium nitroprusside were similar in healthy control and Ass-KOTie2 mice. However, in diabetic Ass-KOTie2 mice, relaxation responses to acetylcholine and endothelium-derived NO (EDNO) were significantly reduced when compared to diabetic control mice.ConclusionsAbsence of endothelial citrulline recycling to arginine did not affect blood pressure and systemic arterial vasomotor responses in healthy mice. EDNO-mediated vasodilatation was significantly more impaired in diabetic Ass-KOTie2 than in control mice demonstrating that endothelial arginine recycling becomes a limiting endothelial function in diabetes.
Highlights
The endothelium regulates vasomotor tone by releasing several relaxing and contractile factors (EDCF)
endothelium-derived nitric oxide (NO) (EDNO)-mediated vasodilatation was significantly more impaired in diabetic Ass-KOTie2 than in control mice demonstrating that endothelial arginine recycling becomes a limiting endothelial function in diabetes
We have previously shown that Assfl/fl mice are indistinguishable from their wild type littermates [23]. 12- and 34-week-old male and female mice were used for the experiments
Summary
The endothelium regulates vasomotor tone by releasing several relaxing (endothelium-derived relaxing factors, EDRF) and contractile factors (EDCF). Reported intracellular concentrations of arginine vary between 300 [10] and 800 mM [11], which is much higher than the Km (3 mM) for endothelial NOS (NOS3) Despite this high intracellular arginine concentration, improved NO production [11] or improved endothelial function of small coronary vessels [12] have been reported after arginine supplementation. This phenomenon, which is known as the arginine paradox [13,14], shows that the intracellular arginine concentration can become limiting under some conditions. Intracellular availability of arginine depends on transport, recycling, metabolism and catabolism [15]
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