{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T21:33:53Z","timestamp":1776720833927,"version":"3.51.2"},"reference-count":49,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:00:00Z","timestamp":1635897600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["VENI 916.76.191"],"award-info":[{"award-number":["VENI 916.76.191"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 \u03bcg 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\u2212\/\u2212 compared to Nos2\u2212\/\u2212 mice. Jejunal NO production and the microcirculation were significantly decreased in control and Nos2\u2212\/\u2212 mice after LPS infusion. No beneficial effects of L-citrulline supplementation on microcirculatory flow were found in Nos3\u2212\/\u2212 or Nos2\u2212\/\u2212\/Nos3\u2212\/\u2212 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\u2212\/\u2212 mice), as this beneficial effect was absent in Nos3\u2212\/\u2212 or Nos2\u2212\/\u2212\/Nos3\u2212\/\u2212 mice.<\/jats:p>","DOI":"10.3390\/ijms222111940","type":"journal-article","created":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T17:59:38Z","timestamp":1635962378000},"page":"11940","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Microcirculatory Function during Endotoxemia\u2014A Functional Citrulline-Arginine-NO Pathway and NOS3 Complex Is Essential to Maintain the Microcirculation"],"prefix":"10.3390","volume":"22","author":[{"given":"Karolina A. P.","family":"Wijnands","sequence":"first","affiliation":[{"name":"Department of Surgery, NUTRIM School of Nutrition, Translational Research in Metabolism, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1781-1363","authenticated-orcid":false,"given":"Dennis M.","family":"Meesters","sequence":"additional","affiliation":[{"name":"Department of Surgery, NUTRIM School of Nutrition, Translational Research in Metabolism, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands"},{"name":"Department of Genetics & Cell Biology, NUTRIM School of Nutrition, Translational Research in Metabolism, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Vandendriessche","sequence":"additional","affiliation":[{"name":"VIB Inflammation Research Center, 9052 Ghent, Belgium"},{"name":"Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium"},{"name":"Byteflies, 2600 Antwerp, Belgium"},{"name":"Department of Electrical, Computer and Systems Engineering, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1405-5232","authenticated-orcid":false,"given":"Jacob J.","family":"Bried\u00e9","sequence":"additional","affiliation":[{"name":"Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans M. H.","family":"van Eijk","sequence":"additional","affiliation":[{"name":"Department of Surgery, NUTRIM School of Nutrition, Translational Research in Metabolism, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Brouckaert","sequence":"additional","affiliation":[{"name":"VIB Inflammation Research Center, 9052 Ghent, Belgium"},{"name":"Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anje","family":"Cauwels","sequence":"additional","affiliation":[{"name":"VIB Inflammation Research Center, 9052 Ghent, Belgium"},{"name":"Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium"},{"name":"Orionis Biosciences, 9052 Ghent, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3032-7824","authenticated-orcid":false,"given":"Wouter H.","family":"Lamers","sequence":"additional","affiliation":[{"name":"Department of Anatomy & Embryology, NUTRIM School of Nutrition, Translational Research in Metabolism, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5005-1285","authenticated-orcid":false,"given":"Martijn","family":"Poeze","sequence":"additional","affiliation":[{"name":"Department of Surgery, NUTRIM School of Nutrition, Translational Research in Metabolism, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/j.1553-2712.2008.00109.x","article-title":"Resuscitating the microcirculation in sepsis: The central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials","volume":"15","author":"Trzeciak","year":"2008","journal-title":"Acad. 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