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.