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• W4225385497 abstract "A reduction in blood flow to the brain in hypertension leads to vascular dementia, but what drives this is unknown. In vascular smooth muscle cells (VSMCs) the close spatial coupling (~20 nm) between Ca2+ release events from the sarcoplasmic reticulum (SR) (Ca2+ sparks) and the vasodilatory large-conductance Ca2+ activated K+ (BK) channels, buffers pressure induced constriction and ensures correct cerebral perfusion.Impaired BK channel activation was responsible for the impaired cerebral autoregulation in hypertension-induced dementia.Male hypertensive mice (BPH/2) and the normotensive control strain (BPN/3) were euthanized in adhered to the UK Home Office Guidance on the Operation of the Animals (Scientific Procedures) Act 1986. Experiments were carried out using pressure myography, confocal microscopy and electrophysiology techniques.Pressure-induced contraction was studied at a range of intraluminal pressures (10-120 mmHg), and cerebral arteries from BPH/2 mice showed a more contractile phenotype compared to BPN/3 controls, confirming impaired autoregulation. BK channel activation by Ca2+ sparks was recorded using perforated patch electrophysiology to record spontaneous transient outward currents (STOCs). STOCs recorded from VSMCs from BPH/2 cerebral arteries, showed a significant reduction in both frequency and amplitude. To determine the mechanism behind this loss of BK activity, we first studied Ca2+ sparks in pressurised cerebral arteries loaded with Fluro-4-AM and found no difference between BPH/2 and BPN/3 mice. Next, we looked at BK alpha subunit expression, by recording whole cell BK currents with a fixed [Ca2+ ] in the pipette solution. Paradoxically, there was an increase in BK current density in the VSMC from the BPH/2 mice compare to BPN/3 mice. We then looked at the Ca2+ sensitivity of the BK channel using single channel electrophysiology, but again there were no differences between the BPH/2 and BPN/3 groups. Subsequently we used live-cell fluorescent membrane dyes to look at the coupling between the SR (ER-Tracker) and the plasma membrane (CellMask) in freshly isolated VSMCs. 3D reconstruction of the deconvolved images showed a reduction in both the coupling site volume and frequency in cells isolated from BPH/2 mice.This data suggests that an increased spatial distance between the SR and the plasma membrane reduces [Ca2+ ] around the BK channel resulting in increased constriction of the arteries. Opportunities to restore the spark-to-BK coupling could be a novel approach to prevent vascular dementia caused by hypertension." @default.
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• W4225385497 date "2022-05-01" @default.
• W4225385497 modified "2023-09-26" @default.
• W4225385497 title "Loss of Ca ²⁺ spark‐to‐BK channel coupling impairs cerebral autoregulation in hypertension" @default.
• W4225385497 doi "https://doi.org/10.1096/fasebj.2022.36.s1.r1906" @default.
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