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Article

Microcirculatory Function during Endotoxemia—A Functional Citrulline-Arginine-NO Pathway and NOS3 Complex Is Essential to Maintain the Microcirculation

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Department of Surgery, NUTRIM School of Nutrition, Translational Research in Metabolism, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands
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Department of Genetics & Cell Biology, NUTRIM School of Nutrition, Translational Research in Metabolism, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands
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VIB Inflammation Research Center, 9052 Ghent, Belgium
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Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium
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Byteflies, 2600 Antwerp, Belgium
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Department of Electrical, Computer and Systems Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
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Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands
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Orionis Biosciences, 9052 Ghent, Belgium
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Department of Anatomy & Embryology, NUTRIM School of Nutrition, Translational Research in Metabolism, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands
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Author to whom correspondence should be addressed.
Academic Editor: Tzong-Shyuan Lee
Int. J. Mol. Sci. 2021, 22(21), 11940; https://doi.org/10.3390/ijms222111940
Received: 28 August 2021 / Revised: 1 November 2021 / Accepted: 1 November 2021 / Published: 3 November 2021
(This article belongs to the Special Issue Nitric Oxide Synthases: Regulation and Function 2021)
Competition for the amino acid arginine by endothelial nitric-oxide synthase (NOS3) and (pro-)inflammatory NO-synthase (NOS2) during endotoxemia appears essential in the derangement of the microcirculatory flow. This study investigated the role of NOS2 and NOS3 combined with/without citrulline supplementation on the NO-production and microcirculation during endotoxemia. Wildtype (C57BL6/N background; control; n = 36), Nos2-deficient, (n = 40), Nos3-deficient (n = 39) and Nos2/Nos3-deficient mice (n = 42) received a continuous intravenous LPS infusion alone (200 μg total, 18 h) or combined with L-citrulline (37.5 mg, last 6 h). The intestinal microcirculatory flow was measured by side-stream dark field (SDF)-imaging. The jejunal intracellular NO production was quantified by in vivo NO-spin trapping combined with electron spin-resonance (ESR) spectrometry. Amino-acid concentrations were measured by high-performance liquid chromatography (HPLC). LPS infusion decreased plasma arginine concentration in control and Nos3−/− compared to Nos2−/− mice. Jejunal NO production and the microcirculation were significantly decreased in control and Nos2−/− mice after LPS infusion. No beneficial effects of L-citrulline supplementation on microcirculatory flow were found in Nos3−/− or Nos2−/−/Nos3−/− mice. This study confirms that L-citrulline supplementation enhances de novo arginine synthesis and NO production in mice during endotoxemia with a functional NOS3-enzyme (control and Nos2−/− mice), as this beneficial effect was absent in Nos3−/− or Nos2−/−/Nos3−/− mice. View Full-Text
Keywords: nitric oxide synthase; arginine; microcirculation; endotoxemia; citrulline; NOS3; NOS2 nitric oxide synthase; arginine; microcirculation; endotoxemia; citrulline; NOS3; NOS2
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MDPI and ACS Style

Wijnands, K.A.P.; Meesters, D.M.; Vandendriessche, B.; Briedé, J.J.; van Eijk, H.M.H.; Brouckaert, P.; Cauwels, A.; Lamers, W.H.; Poeze, M. Microcirculatory Function during Endotoxemia—A Functional Citrulline-Arginine-NO Pathway and NOS3 Complex Is Essential to Maintain the Microcirculation. Int. J. Mol. Sci. 2021, 22, 11940. https://doi.org/10.3390/ijms222111940

AMA Style

Wijnands KAP, Meesters DM, Vandendriessche B, Briedé JJ, van Eijk HMH, Brouckaert P, Cauwels A, Lamers WH, Poeze M. Microcirculatory Function during Endotoxemia—A Functional Citrulline-Arginine-NO Pathway and NOS3 Complex Is Essential to Maintain the Microcirculation. International Journal of Molecular Sciences. 2021; 22(21):11940. https://doi.org/10.3390/ijms222111940

Chicago/Turabian Style

Wijnands, Karolina A.P., Dennis M. Meesters, Benjamin Vandendriessche, Jacob J. Briedé, Hans M.H. van Eijk, Peter Brouckaert, Anje Cauwels, Wouter H. Lamers, and Martijn Poeze. 2021. "Microcirculatory Function during Endotoxemia—A Functional Citrulline-Arginine-NO Pathway and NOS3 Complex Is Essential to Maintain the Microcirculation" International Journal of Molecular Sciences 22, no. 21: 11940. https://doi.org/10.3390/ijms222111940

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