{"title":"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","authors":"Md A. Hakim, Erik J. Behringer","doi":"10.1111/micc.12797","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Objective</h3>\n \n <p>Endothelial cell (EC) coupling occurs through gap junctions and underlies cerebral blood flow regulation governed by inward-rectifying K<sup>+</sup> (K<sub>IR</sub>) channels. This study addressed effects of K<sub>IR</sub> channel activity on EC coupling before and during Alzheimer's disease (AD).</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>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 <i>3xTg-AD</i> mice. Dual intracellular microelectrodes applied simultaneous current injections (±0.5–3 nA) and membrane potential (V<sub>m</sub>) recordings in ECs at distance ~400 μm. Elevated extracellular potassium ([K<sup>+</sup>]<sub>E</sub>; 8–15 mmol/L; reference, 5 mmol/L) activated K<sub>IR</sub> channels.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Conducted V<sub>m</sub> (∆V<sub>m</sub>) responses ranged from ~−30 to 30 mV in response to −3 to +3 nA (linear regression, <i>R</i><sup>2</sup> ≥ .99) while lacking rectification for charge polarity or axial direction of spread. Conduction slope decreased ~10%–20% during 15 mmol/L [K<sup>+</sup>]<sub>E</sub> in Pre-AD males and AD females. 15 mmol/L [K<sup>+</sup>]<sub>E</sub> decreased conduction by ~10%–20% at lower ∆V<sub>m</sub> thresholds in AD animals (~±20 mV) versus Pre-AD (~±25 mV). AD increased conducted hyperpolarization by ~10%–15% during 8–12 mmol/L [K<sup>+</sup>]<sub>E</sub>.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Brain endothelial K<sub>IR</sub> channel activity modulates bidirectional spread of vasoreactive signals with enhanced regulation of EC coupling during AD pathology.</p>\n </section>\n </div>","PeriodicalId":18459,"journal":{"name":"Microcirculation","volume":null,"pages":null},"PeriodicalIF":1.9000,"publicationDate":"2022-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/micc.12797","citationCount":"1","resultStr":"{\"title\":\"KIR channel regulation of electrical conduction along cerebrovascular endothelium: Enhanced modulation during Alzheimer's disease\",\"authors\":\"Md A. Hakim, Erik J. Behringer\",\"doi\":\"10.1111/micc.12797\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Objective</h3>\\n \\n <p>Endothelial cell (EC) coupling occurs through gap junctions and underlies cerebral blood flow regulation governed by inward-rectifying K<sup>+</sup> (K<sub>IR</sub>) channels. This study addressed effects of K<sub>IR</sub> channel activity on EC coupling before and during Alzheimer's disease (AD).</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>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 <i>3xTg-AD</i> mice. Dual intracellular microelectrodes applied simultaneous current injections (±0.5–3 nA) and membrane potential (V<sub>m</sub>) recordings in ECs at distance ~400 μm. Elevated extracellular potassium ([K<sup>+</sup>]<sub>E</sub>; 8–15 mmol/L; reference, 5 mmol/L) activated K<sub>IR</sub> channels.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Conducted V<sub>m</sub> (∆V<sub>m</sub>) responses ranged from ~−30 to 30 mV in response to −3 to +3 nA (linear regression, <i>R</i><sup>2</sup> ≥ .99) while lacking rectification for charge polarity or axial direction of spread. Conduction slope decreased ~10%–20% during 15 mmol/L [K<sup>+</sup>]<sub>E</sub> in Pre-AD males and AD females. 15 mmol/L [K<sup>+</sup>]<sub>E</sub> decreased conduction by ~10%–20% at lower ∆V<sub>m</sub> thresholds in AD animals (~±20 mV) versus Pre-AD (~±25 mV). AD increased conducted hyperpolarization by ~10%–15% during 8–12 mmol/L [K<sup>+</sup>]<sub>E</sub>.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>Brain endothelial K<sub>IR</sub> channel activity modulates bidirectional spread of vasoreactive signals with enhanced regulation of EC coupling during AD pathology.</p>\\n </section>\\n </div>\",\"PeriodicalId\":18459,\"journal\":{\"name\":\"Microcirculation\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2022-12-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/micc.12797\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Microcirculation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/micc.12797\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Microcirculation","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/micc.12797","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"HEMATOLOGY","Score":null,"Total":0}
KIR channel regulation of electrical conduction along cerebrovascular endothelium: Enhanced modulation during Alzheimer's disease
Objective
Endothelial cell (EC) coupling occurs through gap junctions and underlies cerebral blood flow regulation governed by inward-rectifying K+ (KIR) channels. This study addressed effects of KIR 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 (Vm) recordings in ECs at distance ~400 μm. Elevated extracellular potassium ([K+]E; 8–15 mmol/L; reference, 5 mmol/L) activated KIR channels.
Results
Conducted Vm (∆Vm) 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 ∆Vm 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 KIR channel activity modulates bidirectional spread of vasoreactive signals with enhanced regulation of EC coupling during AD pathology.
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.