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Endothelial arginine resynthesis contributes to the maintenance of vasomotor function in male diabetic mice

Argininosuccinate 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. Endothelium-sele...

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Bibliographic Details
Published in:	PloS one 2014-07, Vol.9 (7), p.e102264
Main Authors:	Chennupati, Ramesh, Meens, Merlijn J P M T, Marion, Vincent, Janssen, Ben J, Lamers, Wouter H, De Mey, Jo G R, Köhler, S Eleonore
Format:	Article
Language:	English
Subjects:	Acetylcholine Acetylcholine - pharmacology Animals Arginase Arginase - metabolism Arginine Arginine - biosynthesis Arginine - blood Argininosuccinate Synthase - genetics Arteries Blood Blood pressure Blood Pressure - genetics Blood Pressure - physiology Citrulline Citrulline - blood Citrulline - metabolism Contractility Diabetes Diabetes mellitus Diabetes Mellitus, Experimental - genetics Diabetes Mellitus, Experimental - metabolism Diabetes therapy Embryology Endothelial cells Endothelial Cells - cytology Endothelial Cells - enzymology Endothelium Endothelium - cytology Endothelium - enzymology Endothelium - metabolism Experiments Female Heart Rate - genetics Heart Rate - physiology Hypertension Immunohistochemistry Immunology Ligases Male Medicine and Health Sciences Metabolism Mice Mice, Knockout Muscle, Smooth, Vascular - physiology NG-Nitroarginine Methyl Ester Nitric oxide Nitric Oxide Synthase - antagonists & inhibitors Nitric Oxide Synthase - metabolism Nitric-oxide synthase Nitroprusside - pharmacology Nutrition Pharmacology Phenylephrine Phenylephrine - pharmacology Rodent control Rodents Sodium Sodium nitroprusside Streptozocin Substrates Thoracic surgery Toxicology Vasoconstrictor Agents - pharmacology Vasodilation Vasodilation - genetics Vasodilation - physiology Vasodilator Agents - pharmacology Vasomotor System - metabolism Veins & arteries
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Summary:	Argininosuccinate 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. Endothelium-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. Absence 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.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0102264