@article{ref1,
title="Traumatic brain injury impairs myogenic constriction of cerebral arteries: role of mitochondria-derived H2O2 and TRPV4-dependent activation of BKCa channels",
journal="Journal of neurotrauma",
year="2018",
author="Szarka, Nikolett and Pabbidi, Mallikarjuna R. and Amrein, Krisztina and Czeiter, Endre and Berta, Gergely and Pohoczky, Krisztina and Helyes, Zsuzsanna and Ungvari, Zoltan and Koller, Akos and Büki, Andras and Toth, Peter",
volume="ePub",
number="ePub",
pages="ePub-ePub",
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 (24 h post-impact). We found that post-TBI MCAs exhibited impaired myogenic constriction, which was restored by treatment with a mitochondria-targeted antioxidant (mitoTEMPO), by scavenging of H2O2 (PEG-catalase) and by blocking both BKCa channels (paxilline) and TRPV4 channels (HC067047). 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.<p /> <p>Language: en</p>",
language="en",
issn="0897-7151",
doi="10.1089/neu.2017.5056",
url="http://dx.doi.org/10.1089/neu.2017.5056"
}