title: Traumatic Brain Injury Causes Endothelial Dysfunction in the Systemic Microcirculation through Arginase-1-Dependent Uncoupling of Endothelial Nitric Oxide Synthase.
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.
authors.affiliation: 1 Department of Pharmacology, University of Vermont , Burlington, Vermont.
authors.forename: Nuria
authors.initials: N
authors.lastname: Villalba
authors.affiliation: 2 Department of Surgery, University of Vermont , Burlington, Vermont.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Sackheim
authors.affiliation: 2 Department of Surgery, University of Vermont , Burlington, Vermont.
authors.forename: Ivette A
authors.initials: IA
authors.lastname: Nunez
authors.affiliation: 1 Department of Pharmacology, University of Vermont , Burlington, Vermont.
authors.forename: David C
authors.initials: DC
authors.lastname: Hill-Eubanks
authors.affiliation: 1 Department of Pharmacology, University of Vermont , Burlington, Vermont.|2 Department of Surgery, University of Vermont , Burlington, Vermont.|3 Institute of Cardiovascular Sciences, University of Manchester , Manchester, United Kingdom .
authors.forename: Mark T
authors.initials: MT
authors.lastname: Nelson
authors.affiliation: 1 Department of Pharmacology, University of Vermont , Burlington, Vermont.|2 Department of Surgery, University of Vermont , Burlington, Vermont.
authors.forename: George C
authors.initials: GC
authors.lastname: Wellman
authors.affiliation: 1 Department of Pharmacology, University of Vermont , Burlington, Vermont.|2 Department of Surgery, University of Vermont , Burlington, Vermont.
authors.forename: Kalev
authors.initials: K
authors.lastname: Freeman
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001119:Arginase / Q000378:metabolism*; D000070642:Brain Injuries, Traumatic / Q000201:enzymology* / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D001119:Arginase; C542908:arginase I, rat; D000109:Acetylcholine
keywords: in vitro studies; oxidative stress; traumatic brain injury; vascular injury; vascular reactivity