Traumatic Brain Injury Causes Endothelial Dysfunction in the Systemic Microcirculation through Arginase-1–Dependent Uncoupling of Endothelial Nitric Oxide Synthase
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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
- 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 · 2016: 1
- 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 › 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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