Cited by 101Nitric Oxide and Endothelin EffectsTraumatic Brain Injury and Neurovascular DisturbancesCardiovascular Health and Disease Prevention

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Traumatic Brain Injury Causes Endothelial Dysfunction in the Systemic Microcirculation through Arginase-1–Dependent Uncoupling of Endothelial Nitric Oxide Synthase

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Villalba, Nuria, Sackheim, Adrian M., Nunez, Ivette A., Hill-Eubanks, David C., Nelson, Mark T., Wellman, George C., Freeman, Kalev·2017·Journal of Neurotrauma

DOI 10.1089/neu.2015.4340PMC PMC5198065

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Abstract

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.

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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
ORCID: Villalba, Nuria
Nelson, Mark T.
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
DOI: 10.1089/neu.2015.4340
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
Licence: www.liebertpub.com/nv/resources-tools/text-and-data-mining-policy/121/ (tdm)
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

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Traumatic Brain Injury Causes Endothelial Dysfunction in the Systemic Microcirculation through Arginase-1–Dependent Uncoupling of Endothelial Nitric Oxide Synthase

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