Traumatic Brain Injury Impairs Systemic Vascular Function Through Altered Lipid Metabolism and Disruption of Inward-Rectifier Potassium (Kir2.1) Channels

AbstractBACKGROUND AND PURPOSETrauma can lead to widespread vascular endothelial dysfunction, but the underlying mechanisms remain largely unknown. Strong inward-rectifier potassium channels (Kir2.1) play a critical role in the dynamic regulation of regional perfusion and blood flow. Kir2.1 channel activity is modulated by phosphatidylinositol 4,5-bisphosphate (PIP2), a minor membrane phospholipid that is degraded by phospholipase A2 (PLA2) in conditions of oxidative stress or severe inflammation. We hypothesized that PLA2–induced depletion of PIP2 impairs Kir2.1 channel function.METHODSA fluid percussion injury model of traumatic brain injury (TBI) in rats was used to study mesenteric resistance arteries 24 hours after injury. Patch-clamp electrophysiology in freshly isolated endothelial and smooth muscle cells was performed to monitor Kir2.1 conductance, and the functional responses of intact arteries were assessed using pressure myography. We analyzed circulating PLA2, hydrogen peroxide (H2O2), and metabolites to identify alterations in signaling pathways associated with PIP2 in TBI.RESULTSElectrophysiology analysis of endothelial and smooth muscle cells revealed a significant reduction of Ba2+-sensitive Kir2.1 currents after TBI. Additionally, dilations to elevated extracellular potassium and BaCl2- 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 PIP2 analog to the patch pipette successfully rescued endothelial Kir2.1 currents after TBI. Both H2O2 and PLA2 activity were increased after injury. Metabolomics analysis demonstrated altered lipid metabolism signaling pathways, including increased arachidonic acid, and fatty acid mobilization after TBI.CONCLUSIONSOur findings support a model in which increased H2O2-induced PLA2 activity after trauma hydrolyzes endothelial PIP2, resulting in impaired Kir2.1 channel function.

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

Function ◽

10.1093/function/zqab018 ◽

2021 ◽

Author(s):

Adrian M Sackheim ◽

Nuria Villalba ◽

Maria Sancho ◽

Osama F Harraz ◽

Adrian D Bonev ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Potassium Channels ◽

Signaling Pathways ◽

Inward Rectifier ◽

Pla2 Activity ◽

Functional Responses ◽

Channel Function ◽

Inward Rectifier Potassium Channels ◽

Kir2.1 Channel

Abstract 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 (PIP2), a membrane phospholipid that is degraded by phospholipase A2 (PLA2) in conditions of oxidative stress or inflammation. We hypothesized that PLA2–induced depletion of PIP2 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 hours after injury. The functional responses of intact arteries were assessed using pressure myography. We analyzed circulating PLA2, hydrogen peroxide (H2O2), and metabolites to identify alterations in signaling pathways associated with PIP2 in TBI. Electrophysiology analysis of freshly-isolated endothelial and smooth muscle cells revealed a significant reduction of Ba2+-sensitive Kir2.1 currents after TBI. Additionally, dilations to elevated extracellular potassium and BaCl2- 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 PIP2 analog to the patch pipette successfully rescued endothelial Kir2.1 currents after TBI. Both H2O2 and PLA2 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 H2O2-induced PLA2 activity after trauma hydrolyzes endothelial PIP2, resulting in impaired Kir2.1 channel function.

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Altered lipid metabolism as potential biomarker of poor outcome in sever traumatic brain injury (Pilot study)

Clinical Nutrition ESPEN ◽

10.1016/j.clnesp.2020.09.320 ◽

2020 ◽

Vol 40 ◽

pp. 512-513

Author(s):

V. Hancharou ◽

V. Sviatlitskaya ◽

S. Komlikau

Keyword(s):

Traumatic Brain Injury ◽

Lipid Metabolism ◽

Brain Injury ◽

Pilot Study ◽

Poor Outcome ◽

Potential Biomarker ◽

Altered Lipid Metabolism ◽

Altered Lipid

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Pathologically Entangled: Brain trauma-evoked ROS imbalance disrupts Kir channel function in distant peripheral vessels

Function ◽

10.1093/function/zqab021 ◽

2021 ◽

Author(s):

Nick Weir ◽

Thomas A Longden

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Potassium Channels ◽

Vascular Function ◽

Inward Rectifier ◽

Brain Trauma ◽

Channel Function ◽

Inward Rectifier Potassium Channels ◽

Kir Channel

Abstract A Perspective on "Traumatic Brain Injury Impairs Systemic Vascular Function Through Disruption of Inward-Rectifier Potassium Channels"

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Impaired capillary-to-arteriolar electrical signaling after traumatic brain injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20962594 ◽

2020 ◽

pp. 0271678X2096259

Author(s):

Amreen Mughal ◽

Adrian M Sackheim ◽

Maria Sancho ◽

Thomas A Longden ◽

Sheila Russell ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Cerebral Hemodynamics ◽

Laser Scanning Microscopy ◽

Functional Hyperemia ◽

Cranial Window ◽

Channel Function ◽

Inward Rectifier Potassium Channels ◽

Electrical Signaling ◽

Kir2.1 Channel

Traumatic brain injury (TBI) acutely impairs dynamic regulation of local cerebral blood flow, but long-term (>72 h) effects on functional hyperemia are unknown. Functional hyperemia depends on capillary endothelial cell inward rectifier potassium channels (Kir2.1) responding to potassium (K+) released during neuronal activity to produce a regenerative, hyperpolarizing electrical signal that propagates from capillaries to dilate upstream penetrating arterioles. We hypothesized that TBI causes widespread disruption of electrical signaling from capillaries-to-arterioles through impairment of Kir2.1 channel function. We randomized mice to TBI or control groups and allowed them to recover for 4 to 7 days post-injury. We measured in vivo cerebral hemodynamics and arteriolar responses to local stimulation of capillaries with 10 mM K+ using multiphoton laser scanning microscopy through a cranial window under urethane and α-chloralose anesthesia. Capillary angio-architecture was not significantly affected following injury. However, K+-induced hyperemia was significantly impaired. Electrophysiology recordings in freshly isolated capillary endothelial cells revealed diminished Ba2+-sensitive Kir2.1 currents, consistent with a reduction in channel function. In pressurized cerebral arteries isolated from TBI mice, K+ failed to elicit the vasodilation seen in controls. We conclude that disruption of endothelial Kir2.1 channel function impairs capillary-to-arteriole electrical signaling, contributing to altered cerebral hemodynamics after TBI.

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