KIR channel regulation of electrical conduction along cerebrovascular endothelium: Enhanced modulation during Alzheimer's disease

IF 1.9 4区医学 Q3 HEMATOLOGY

Microcirculation Pub Date : 2022-12-28 DOI:10.1111/micc.12797

Md A. Hakim, Erik J. Behringer

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引用次数: 1

Abstract

Objective

Endothelial cell (EC) coupling occurs through gap junctions and underlies cerebral blood flow regulation governed by inward-rectifying K⁺ (K_IR) channels. This study addressed effects of K_IR channel activity on EC coupling before and during Alzheimer's disease (AD).

Methods

Intact EC tubes (width: ~90–100 μm; length: ~0.5 mm) were freshly isolated from posterior cerebral arteries of young Pre-AD (1–3 months) and aged AD (13–18 months) male and female 3xTg-AD mice. Dual intracellular microelectrodes applied simultaneous current injections (±0.5–3 nA) and membrane potential (V_m) recordings in ECs at distance ~400 μm. Elevated extracellular potassium ([K⁺]_E; 8–15 mmol/L; reference, 5 mmol/L) activated K_IR channels.

Results

Conducted V_m (∆V_m) responses ranged from ~−30 to 30 mV in response to −3 to +3 nA (linear regression, R² ≥ .99) while lacking rectification for charge polarity or axial direction of spread. Conduction slope decreased ~10%–20% during 15 mmol/L [K⁺]_E in Pre-AD males and AD females. 15 mmol/L [K⁺]_E decreased conduction by ~10%–20% at lower ∆V_m thresholds in AD animals (~±20 mV) versus Pre-AD (~±25 mV). AD increased conducted hyperpolarization by ~10%–15% during 8–12 mmol/L [K⁺]_E.

Conclusions

Brain endothelial K_IR channel activity modulates bidirectional spread of vasoreactive signals with enhanced regulation of EC coupling during AD pathology.

Abstract Image

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KIR通道对脑血管内皮传导的调节：阿尔茨海默病期间增强的调节

目的内皮细胞（EC）偶联是通过间隙连接发生的，是由内向整流K+（KIR）通道调控脑血流的基础。这项研究探讨了在阿尔茨海默病（AD）之前和期间KIR通道活性对EC偶联的影响。方法完整的EC管（宽度：~90-100 μm；长度：~0.5 mm）从年轻AD前期（1-3 月）和老年AD（13-18月）雄性和雌性3xTg AD小鼠。双细胞内微电极在距离约400的EC中同时进行电流注入（±0.5–3 nA）和膜电位（Vm）记录 μm。细胞外钾升高（[K+]E；8-15 mmol/L；参考，5 mmol/L）激活KIR通道。结果传导Vm（∆Vm）响应范围从~−30到30 响应−3至+3 nA的mV（线性回归，R2 ≥ .99），同时缺乏对电荷极性或轴向扩展方向的整流。传导斜率在15 AD前期男性和AD女性中的mmol/L[K+]E。15 mmol/L[K+]E使AD动物在较低∆Vm阈值下（~±20 mV）与AD前（~±25 mV）。AD在8-12期间将传导超极化增加了约10%-15% mmol/L[K+]E。结论在AD病理过程中，脑内皮KIR通道活性通过增强EC偶联调节血管反应信号的双向传播。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Microcirculation 医学-外周血管病

CiteScore

5.00

自引率

4.20%

发文量

审稿时长

6-12 weeks

期刊介绍： The journal features original contributions that are the result of investigations contributing significant new information relating to the vascular and lymphatic microcirculation addressed at the intact animal, organ, cellular, or molecular level. Papers describe applications of the methods of physiology, biophysics, bioengineering, genetics, cell biology, biochemistry, and molecular biology to problems in microcirculation. Microcirculation also publishes state-of-the-art reviews that address frontier areas or new advances in technology in the fields of microcirculatory disease and function. Specific areas of interest include: Angiogenesis, growth and remodeling; Transport and exchange of gasses and solutes; Rheology and biorheology; Endothelial cell biology and metabolism; Interactions between endothelium, smooth muscle, parenchymal cells, leukocytes and platelets; Regulation of vasomotor tone; and Microvascular structures, imaging and morphometry. Papers also describe innovations in experimental techniques and instrumentation for studying all aspects of microcirculatory structure and function.