The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.
Traumatic Brain Injury Causes Endothelial Dysfunction in the Systemic Microcirculation through Arginase-1–Dependent Uncoupling of Endothelial Nitric Oxide Synthase
Open accessAbstract
Endothelial dysfunction is a hallmark of many chronic diseases, including diabetes and long-term hypertension. We show that acute traumatic brain injury (TBI) leads to endothelial dysfunction in rat mesenteric arteries. Endothelial-dependent dilation was greatly diminished 24 h after TBI because of impaired nitric oxide (NO) production. The activity of arginase, which competes with endothelial NO synthase (eNOS) for the common substrate l-arginine, were also significantly increased in arteries, suggesting that arginase-mediated depletion of l-arginine underlies diminished NO production. Consistent with this, substrate restoration by exogenous application of l-arginine or inhibition of arginase recovered endothelial function. Moreover, evidence for increased reactive oxygen species production, a consequence of l-arginine starvation-dependent eNOS uncoupling, was detected in endothelium and plasma. Collectively, our findings demonstrate endothelial dysfunction in a remote vascular bed after TBI, manifesting as impaired endothelial-dependent vasodilation, with increased arginase activity, decreased generation of NO, and increased O2- production. We conclude that blood vessels have a “molecular memory” of neurotrauma, 24 h after injury, because of functional changes in vascular endothelial cells; these effects are pertinent to understanding the systemic inflammatory response that occurs after TBI even in the absence of polytrauma.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The text we found for this paper looks like another document, so the self-check wasn’t run.
Citations
Cites
Nitric oxide: physiology, pathophysiology, and pharmacology.
Moncada, S., Palmer, R. M., & Higgs, E. A. (1991) · Pharmacological Reviews · doi:10.1016/s0031-6997(25)06663-3 · Cited by 15,525
Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor
Palmer, R. M. J., Ferrige, A. G., & Moncada, S. (1987) · Nature · doi:10.1038/327524a0 · Cited by 10,704
How mitochondria produce reactive oxygen species
Murphy, M. P. (2009) · Biochemical Journal · doi:10.1042/bj20081386 · Cited by 8,207
Nitric oxide synthases: regulation and function
Forstermann, U., & Sessa, W. C. (2012) · European Heart Journal · doi:10.1093/eurheartj/ehr304 · Cited by 4,409
Arginine metabolism: nitric oxide and beyond
WU, G., & MORRIS, S. M. (1998) · Biochemical Journal · doi:10.1042/bj3360001 · Cited by 2,811
Rajagopalan, S., Kurz, S. D., Münzel, T. F., Tarpey, M. M., Freeman, B. Α., Griendling, K. K., & Harrison, D. G. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118623 · Cited by 2,467
Hypercholesterolemia increases endothelial superoxide anion production.
Ohara, Y., Peterson, T. E., & Harrison, D. G. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116491 · Cited by 1,765
Landmesser, U., Dikalov, S., Price, S. R., McCann, L., Fukai, T., Holland, S. M., Mitch, W. E., & Harrison, D. G. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200314172 · Cited by 1,660
Landmesser, U., Dikalov, S., Price, S. R., McCann, L. A., Fukai, T., Holland, S. M., Mitch, W. E., & Harrison, D. G. (2003) · Journal of Clinical Investigation · doi:10.1172/jci14172 · Cited by 1,652
Nitric Oxide Synthases: Properties and Catalytic Mechanism
Griffith, O. W., & Stuehr, D. J. (1995) · Annual Review of Physiology · doi:10.1146/annurev.ph.57.030195.003423 · Cited by 1,311
Endemann, D. H., & Schiffrin, E. L. (2004) · Journal of the American Society of Nephrology · doi:10.1097/01.asn.0000132474.50966.da · Cited by 1,198
Regulation of Arterial Tone by Activation of Calcium-Dependent Potassium Channels
Brayden, J. E., & Nelson, M. T. (1992) · Science · doi:10.1126/science.1373909 · Cited by 932
Self-citationComparative properties of arginases
Jenkinson, C. P., Grody, W. W., & Cederbaum, S. D. (1996) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/0305-0491(95)02138-8 · Cited by 610
Circulating Histones Are Mediators of Trauma-associated Lung Injury
Abrams, S. T., Zhang, N., Manson, J., Liu, T., Dart, C., Baluwa, F., Wang, S. S., Brohi, K., Kipar, A., Yu, W., et al. (2012) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201206-1037oc · Cited by 583
Stress-Related Cardiomyopathy Syndromes
Bybee, K. A., & Prasad, A. (2008) · Circulation · doi:10.1161/circulationaha.106.677625 · Cited by 575
Elementary Ca 2+ Signals Through Endothelial TRPV4 Channels Regulate Vascular Function
Sonkusare, S. K., Bonev, A. D., Ledoux, J., Liedtke, W., Kotlikoff, M. I., Heppner, T. J., Hill-Eubanks, D. C., & Nelson, M. T. (2012) · Science · doi:10.1126/science.1216283 · Cited by 552
Self-citationRochette, L., Lorin, J., Zeller, M., Guilland, J.-C., Lorgis, L., Cottin, Y., & Vergely, C. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.07.004 · Cited by 456
The neurophysiology of brain injury
Gaetz, M. (2003) · Clinical Neurophysiology · doi:10.1016/s1388-2457(03)00258-x · Cited by 395
Li, H. Z., Meininger, C. J., Hawker, J. R., Haynes, T. E., Kepka‐Lenhart, D., Mistry, S. K., Morris, S. M., & Wu, G. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.280.1.e75 · Cited by 395
Endothelium-derived hyperpolarising factors and associated pathways: a synopsis
Edwards, G., Félétou, M., & Weston, A. H. (2010) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-010-0817-1 · Cited by 360
Schulman, S. P., Becker, L. C., Kass, D. A., Champion, H. C., Terrin, M. L., Forman, S., Ernst, K. V., Kelemen, M. D., Townsend, S. N., Capriotti, A., et al. (2006) · JAMA · doi:10.1001/jama.295.1.58 · Cited by 357
The l-arginine paradox: Importance of the l-arginine/asymmetrical dimethylarginine ratio
BODEBOGER, S., SCALERA, F., & IGNARRO, L. (2007) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2007.03.002 · Cited by 347
Metabolic fate of L-arginine in relation to microbiostatic capability of murine macrophages.
Granger, D. L., Hibbs, J. B., Perfect, J. R., & Durack, D. T. (1990) · Journal of Clinical Investigation · doi:10.1172/jci114422 · Cited by 347
Circulating Catecholamines and Sympathetic Activity after Head Injury
Clifton, G. L., Ziegler, M. G., & Grossman, R. G. (1981) · Neurosurgery · doi:10.1227/00006123-198101000-00003 · Cited by 296
Extracellular histones in tissue injury and inflammation
Allam, R., Kumar, S. V. R., Darisipudi, M. N., & Anders, H. (2014) · Journal of Molecular Medicine · doi:10.1007/s00109-014-1148-z · Cited by 296
Development of a Fluorescent Indicator for Nitric Oxide Based on the Fluorescein Chromophore.
Kojima, H., SAKURAI, K., Kikuchi, K., Kawahara, S., Kirino, Y., Nagoshi, H., Hirata, Y., & Nagano, T. (1998) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.46.373 · Cited by 293
Taylor, M. S., Bonev, A. D., Gross, T. P., Eckman, D. M., Brayden, J. E., Bond, C. T., Adelman, J. P., & Nelson, M. T. (2003) · Circulation Research · doi:10.1161/01.res.0000081980.63146.69 · Cited by 275
Self-citationRenal arginine synthesis: studies in vitro and in vivo.
Dhanakoti, S. N., Brosnan, J. T., Herzberg, G. R., & Brosnan, M. E. (1990) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1990.259.3.e437 · Cited by 213
Mechanical brain injury: the sympathoadrenal response
Rosner, M. J., Newsome, H. H., & Becker, D. P. (1984) · Journal of neurosurgery · doi:10.3171/jns.1984.61.1.0076 · Cited by 209
An Update on the Coagulopathy of Trauma
Maegele, M., Schöchl, H., & Cohen, M. J. M. (2013) · Shock · doi:10.1097/shk.0000000000000088 · Cited by 194
Crane, G. J., Gallagher, N., Dora, K. A., & Garland, C. J. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2003.051896 · Cited by 189
Nitric Oxide in Traumatic Brain Injury
Cherian, L., Hlatky, R., & Robertson, C. S. (2004) · Brain Pathology · doi:10.1111/j.1750-3639.2004.tb00053.x · Cited by 189
Shemyakin, A. S., Kövamees, O., Rafnsson, A. T., Böhm, F., Svenarud, P. K., Settergren, M., Jung, C., & Pernow, J. (2012) · Circulation · doi:10.1161/circulationaha.112.140335 · Cited by 185
The predictive value of catecholamines in assessing outcome in traumatic brain injury
Woolf, P. D., Hamill, R. W., Lee, L. A., Cox, C., & McDonald, J. V. (1987) · Journal of neurosurgery · doi:10.3171/jns.1987.66.6.0875 · Cited by 180
Rat Liver Arginase: Kinetic Mechanism, Alternate Substrates, and Inhibitors
Reczkowski, R. S., & Ash, D. E. (1994) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1994.1276 · Cited by 168
Arginase I Expression and Activity in Human Mononuclear Cells After Injury
Ochoa, J. B., Bernard, A. C., O’Brien, W. E., Griffen, M. M., Maley, M. E., Rockich, A. K., Tsuei, B. J., Boulanger, B. R., Kearney, P. A., & Morris, S. M. (2001) · Annals of Surgery · doi:10.1097/00000658-200103000-00014 · Cited by 168
Endothelium‐dependent hyperpolarizations: Past beliefs and present facts
Félétou, M., & Vanhoutte, P. M. (2007) · Annals of Medicine · doi:10.1080/07853890701491000 · Cited by 160
Cardiovascular response to severe head injury
Clifton, G. L., Robertson, C. S., Kyper, K., Taylor, A. A., DHEKNE, R. D., & Grossman, R. G. (1983) · Journal of neurosurgery · doi:10.3171/jns.1983.59.3.0447 · Cited by 157
Recoupling the Cardiac Nitric Oxide Synthases: Tetrahydrobiopterin Synthesis and Recycling
Alkaitis, M. S., & Crabtree, M. J. (2012) · Current Heart Failure Reports · doi:10.1007/s11897-012-0097-5 · Cited by 144
Endothelium-derived Hyperpolarizing Factor
Bryan, R. M., You, J., Golding, E. M., & Marrelli, S. P. (2005) · Anesthesiology · doi:10.1097/00000542-200506000-00028 · Cited by 125
Hannah, R. M., Dunn, K. M. J., Bonev, A. D., & Nelson, M. T. (2010) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2010.214 · Cited by 124
Self-citationThe systemic response to CNS injury
Anthony, D. C., & Couch, Y. (2014) · Experimental Neurology · doi:10.1016/j.expneurol.2014.03.013 · Cited by 116
The activity of the sympathetic nervous system following severe head injury
Hörtnagl, H., Hammerle, A. F., Hackl, J. M., Brücke, T., Rumpl, E., & Hörtnagl, H. (1980) · Intensive Care Medicine · doi:10.1007/bf01757299 · Cited by 104
Alef, M. J., Vallabhaneni, R., Carchman, E., Morris, S. M., Shiva, S., Wang, Y., Kelley, E. E., Tarpey, M. M., Gladwin, M. T., Tzeng, E., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44079 · Cited by 101
To Give or Not to Give? Lessons from the Arginine Paradox
Dioguardi, F. S. (2011) · Lifestyle Genomics · doi:10.1159/000327777 · Cited by 95
Settergren, M., Böhm, F., Malmström, R. E., Channon, K. M., & Pernow, J. (2008) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2008.08.034 · Cited by 80
Villalba, N., Sonkusare, S. K., Longden, T. A., Tran, T. L., Sackheim, A. M., Nelson, M. T., Wellman, G. C., & Freeman, K. (2014) · Journal of the American Heart Association · doi:10.1161/jaha.114.001474 · Cited by 69
Self-citationRedox balance in the body: An approach to quantitation
Shapiro, H. M. (1972) · Journal of Surgical Research · doi:10.1016/0022-4804(72)90057-1 · Cited by 68
PLASMA OXIDATION-REDUCTION POTENTIAL AND PROTEIN OXIDATION IN TRAUMATIC BRAIN INJURY
Rael, L. T., Bar-Or, R., Mains, C. W., Slone, D. S., Levy, A. S., & Bar‐Or, D. (2009) · Journal of Neurotrauma · doi:10.1089/neu.2008.0816 · Cited by 63
Rael, L. T., Bar-Or, R., Salottolo, K., Mains, C. W., Slone, D. S., Offner, P. J., & Bar‐Or, D. (2009) · Scandinavian Journal of Trauma Resuscitation and Emergency Medicine · doi:10.1186/1757-7241-17-57 · Cited by 62
Intracellular mechanisms involved in the regulation of vascular smooth muscle tone
Walsh, M. P., Kargacin, G. J., Kendrick‐Jones, J., & Lincoln, T. (1995) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y95-072 · Cited by 58
Systemic manifestations of traumatic brain injury.
Gaddam, S. S., Buell, T. J., & Robertson, C. (2015) · Handbook of Clinical Neurology · doi:10.1016/b978-0-444-52892-6.00014-3 · Cited by 57
p38 mitogen-activated protein kinase is involved in arginase-II-mediated eNOS-Uncoupling in Obesity
Yu, Y., Rajapakse, A. G., Montani, J., Yang, Z., & Ming, X. (2014) · Cardiovascular Diabetology · doi:10.1186/s12933-014-0113-z · Cited by 56
Cardiac Reactive Oxygen Species After Traumatic Brain Injury
Larson, B., Stockwell, D. W., Boas, S., Andrews, T. J., Wellman, G. C., Lockette, W. E., & Freeman, K. (2011) · Journal of Surgical Research · doi:10.1016/j.jss.2011.09.056 · Cited by 43
Self-citationL-Arginine-Mediated Vasoreactivity in Patients with a Risk of Stroke
Zimmermann, C., Wimmer, M. L. J., & Haberl, R. L. (2003) · Cerebrovascular Diseases · doi:10.1159/000075781 · Cited by 40
Systemic Arginine Depletion After a Murine Model of Surgery or Trauma
Pribis, J. P., Zhu, X., Yoram Vodovotz, B., & Ochoa, J. B. (2011) · Journal of Parenteral and Enteral Nutrition · doi:10.1177/0148607111414579 · Cited by 38
Okamoto, M., Etani, H., Yagita, Y., Kinoshita, N., & NUKADA, T. (2001) · Gerontology · doi:10.1159/000052786 · Cited by 38
Liu, H., Goodman, J. C., & Robertson, C. S. (2002) · Journal of Neurotrauma · doi:10.1089/089771502753594891 · Cited by 36
The Arginase Pathway in Neonatal Brain Hypoxia-Ischemia
Mike, J. K., Pathipati, P., Russ, J. B., Sheldon, A., & Ferriero, D. M. (2018) · Developmental Neuroscience · doi:10.1159/000496467 · Cited by 29
TACTIC: Trans‐Agency Consortium for Trauma‐Induced Coagulopathy
Mann, K. G., Freeman, K., Mann, K. G., Esmon, C. T., Wisnewski, S., Tracy, R. P., Kindzelski, A. L., Pusateri, A., Banerjee, A., Brass, L. F., et al. (2015) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.12981 · Cited by 19
Self-citationLiu, Y., Gardner, C. R., Laskin, J. D., & Laskin, D. L. (2012) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2012.10.015 · Cited by 19
Confocal myography for the study of hypertensive vascular remodelling.
Arribas, S. M., González, J. M., Briones, A. M., Somoza, B., Daly, C. J., Vila, E., González, M. C., & McGrath, J. C. (2007) · PubMed · Cited by 12
L-arginine reactivity in cerebral vessels after severe traumatic brain injury
Rangel-Castilla, L., Ahmed, O., Goodman, J. C., Gopinath, S. P., Valadka, A. B., & Robertson, C. S. (2010) · Neurological Research · doi:10.1179/016164110x12767786356598 · Cited by 11
Flagged first, then by citations
Research works printed but not linked: 4
- Forstermann U., 2012, Eur. Heart J., 33, 837a
- Arribas S.M., 2007, Clin. Hemorheol. Microcirc., 37, 205
- Dhanakoti S.N., 1990, Am. J. Physiol., 259, E437
- 10.1172/JCI200314172 · DOI · Paper page
Cited by
Sorted by citations
Arginase: A Multifaceted Enzyme Important in Health and Disease
Caldwell, R. W., Rodriguez, P. C., Toque, H. A., Narayanan, S. P., & Caldwell, R. B. (2018) · Physiological Reviews · doi:10.1152/physrev.00037.2016 · Cited by 495
Astrocyte Endfeet in Brain Function and Pathology: Open Questions
Díaz-Castro, B., Robel, S., & Mishra, A. (2023) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-091922-031205 · Cited by 238
Sandsmark, D. K., Bashir, A., Wellington, C. L., & Diaz-Arrastia, R. R. (2019) · Neuron · doi:10.1016/j.neuron.2019.06.002 · Cited by 180
Metabolic Pathways Fueling the Endothelial Cell Drive
Li, X., Kumar, A., & Carmeliet, P. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020518-114731 · Cited by 172
Transient Receptor Potential Canonical (TRPC) Channels: Then and Now
Chen, X., Sooch, G., Demaree, I. S., White, F. A., & Obukhov, A. G. (2020) · Cells · doi:10.3390/cells9091983 · Cited by 154
Metadata
- Authors
- Villalba, N., Sackheim, A. M., Nunez, I. A., Hill-Eubanks, D. C., Nelson, M. T., Wellman, G. C., & Freeman, K.
- Affiliations
- University of Vermont (US)
- Department of Surgery, University of Vermont, Burlington, Vermont.
- Department of Pharmacology, University of Vermont, Burlington, Vermont.
- Corresponding author
- Freeman, Kalev
- Venue
- Journal of Neurotrauma
- Publisher
- SAGE Publications
- Published
- 2017-01
- Volume
- 34
- Issue
- 1
- Pages
- 192-203
- ISSN
- 0897-7151 (ISSN-L)
- 1557-9042
- PMC
- PMC5198065
- OpenAlex
- W2330581287
- Cited by
- 99
- References
- 62
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 10 · 2023: 10 · 2022: 10 · 2021: 14 · 2020: 14 · 2019: 6 · 2018: 6 · 2017: 6
- FWCI
- 5.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neurotrauma (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- Funders
- National Institutes of Health (5p30gm103498-05, 1s10od017969-01)
- National Heart, Lung, and Blood Institute (R01HL044455, P01HL095488, R01HL121706, R01HL098243, UM1HL120877)
- National Institute of General Medical Sciences (P30-GM103498, K08GM098795)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK053832)
- National Center for Research Resources (P20RR016435, P30RR032135)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Keywords
- traumatic brain injury, endothelial dysfunction, arginase-1, endothelial nitric oxide synthase uncoupling, nitric oxide production, L-arginine depletion, reactive oxygen species, endothelium-dependent vasodilation, mesenteric arteries, systemic inflammatory response
- MeSH terms
- Brain Injuries, Traumatic, Acetylcholine, Animals, Arginase, Endothelium, Vascular, Male, Microcirculation, Vasodilation, Rats, Sprague-Dawley, Rats, Nitric Oxide Synthase Type III
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
