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

PloS one (2014-07-18)
Ramesh Chennupati, Merlijn J P M T Meens, Vincent Marion, Ben J Janssen, Wouter H Lamers, Jo G R De Mey, S Eleonore Köhler
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
3-Mercaptopropionic acid, ≥99%
Sigma-Aldrich
Indomethacin, 98.5-100.5% (in accordance with EP)
Supelco
Indomethacin, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
3-Mercaptopropionic acid, ≥99.0% (HPLC)
Sigma-Aldrich
Indomethacin, meets USP testing specifications
USP
Indomethacin, United States Pharmacopeia (USP) Reference Standard
Indomethacin, European Pharmacopoeia (EP) Reference Standard