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J Neurotrauma. 2018 Jan 12. doi: 10.1089/neu.2017.5056. [Epub ahead of print]

Traumatic Brain Injury Impairs Myogenic Constriction of Cerebral Arteries: Role of Mitochondria-Derived H2O2 and TRPV4-Dependent Activation of BKca Channels.

Szarka N1,2,3, Pabbidi MR4, Amrein K1,2, Czeiter E1,2,5, Berta G6, Pohoczky K7,8, Helyes Z7,8, Ungvari Z9, Koller A1,10,11, Buki A1,2, Toth P1,2,3,5,9.

Author information

1
1 Cerebrovascular Laboratory, Department of Neurosurgery, Medical School University of Pecs, Pecs. Hungary.
2
2 Neurotrauma Research Group, Janos Szentagothai Research Center, Medical School University of Pecs, Pecs. Hungary.
3
3 Department of Translational Medicine, Medical School University of Pecs, Pecs. Hungary.
4
4 Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi.
5
5 MTA-PTE Clinical Neuroscience MR Research Group , Pecs, Hungary .
6
6 Department of Medical Biology, Medical School University of Pecs, Pecs. Hungary.
7
7 Department of Pharmacology and Pharmacotherapy, Medical School University of Pecs, Pecs. Hungary.
8
8 MTA-PTE NAP B Chronic Pain Research Group , Pecs, Hungary .
9
9 Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center , Oklahoma City, Oklahoma.
10
10 Institute of Natural Sciences, University of Physical Education , Budapest, Hungary .
11
11 Department of Physiology, New York Medical College , Valhalla, New York.

Abstract

Traumatic brain injury (TBI) impairs autoregulation of cerebral blood flow, which contributes to the development of secondary brain injury, increasing mortality of patients. Impairment of pressure-induced myogenic constriction of cerebral arteries plays a critical role in autoregulatory dysfunction; however, the underlying cellular and molecular mechanisms are not well understood. To determine the role of mitochondria-derived H2O2 and large-conductance calcium-activated potassium channels (BKCa) in myogenic autoregulatory dysfunction, middle cerebral arteries (MCAs) were isolated from rats with severe weight drop-impact acceleration brain injury. We found that 24 h post-TBI MCAs exhibited impaired myogenic constriction, which was restored by treatment with a mitochondria-targeted antioxidant (mitoTEMPO), by scavenging of H2O2 (polyethylene glycol [PEG]-catalase) and by blocking both BKCa channels (paxilline) and transient receptor potential cation channel subfamily V member 4 (TRPV4) channels (HC 067047). Further, exogenous administration of H2O2 elicited significant dilation of MCAs, which was inhibited by blocking either BKCa or TRPV4 channels. Vasodilation induced by the TRPV4 agonist GSK1016790A was inhibited by paxilline. In cultured vascular smooth muscle cells H2O2 activated BKCa currents, which were inhibited by blockade of TRPV4 channels. Collectively, our results suggest that after TBI, excessive mitochondria-derived H2O2 activates BKCa channels via a TRPV4-dependent pathway in the vascular smooth muscle cells, which impairs pressure-induced constriction of cerebral arteries. Future studies should elucidate the therapeutic potential of pharmacological targeting of this pathway in TBI, to restore autoregulatory function in order to prevent secondary brain damage and decrease mortality.

KEYWORDS:

autoregulation; intracranial hypertension; oxidative stress; secondary injury

PMID:
29179622
PMCID:
PMC5865628
[Available on 2019-04-01]
DOI:
10.1089/neu.2017.5056

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