Traumatic Brain Injury Impairs Systemic Vascular Function through Disruption of Inward-Rectifier Potassium Channels

Trauma can lead to widespread vascular dysfunction, but the underlying mechanisms remain largely unknown. Inward-rectifier potassium channels (Kir2.1) play a critical role in the dynamic regulation of regional perfusion and blood flow. Kir2.1 channel activity requires phosphatidylinositol 4,5-bisphosphate (PIP(2)), a membrane phospholipid that is degraded by phospholipase A(2) (PLA(2)) in conditions of oxidative stress or inflammation. We hypothesized that PLA(2)-induced depletion of PIP(2) after trauma impairs Kir2.1 channel function. A fluid percussion injury model of traumatic brain injury (TBI) in rats was used to study mesenteric resistance arteries 24 h after injury. The functional responses of intact arteries were assessed using pressure myography. We analyzed circulating PLA(2), hydrogen peroxide (H(2)O(2)), and metabolites to identify alterations in signaling pathways associated with PIP(2) in TBI. Electrophysiology analysis of freshly-isolated endothelial and smooth muscle cells revealed a significant reduction of Ba(2+)-sensitive Kir2.1 currents after TBI. Additionally, dilations to elevated extracellular potassium and BaCl(2)- or ML 133-induced constrictions in pressurized arteries were significantly decreased following TBI, consistent with an impairment of Kir2.1 channel function. The addition of a PIP(2) analog to the patch pipette successfully rescued endothelial Kir2.1 currents after TBI. Both H(2)O(2) and PLA(2) activity were increased after injury. Metabolomics analysis demonstrated altered lipid metabolism signaling pathways, including increased arachidonic acid, and fatty acid mobilization after TBI. Our findings support a model in which increased H(2)O(2)-induced PLA(2) activity after trauma hydrolyzes endothelial PIP(2), resulting in impaired Kir2.1 channel function.