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

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

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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Crossref · 10.1089/neu.2015.4340

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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
Venue
Journal of Neurotrauma
Published
2017-01
Volume
34
Issue
1
Pages
192-203
ISSN
  • 0897-7151 (ISSN-L)
  • 1557-9042
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 · 2016: 1
FWCI
5.10
Type
journal article
Language
en
Open access
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 › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › 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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