Inwardly rectifying K+ channels are major contributors to flow-induced vasodilatation in resistance arteries
Inwardly rectifying K+ channels are major contributors to flow-induced vasodilatation in resistance arteries
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DOI：
10.1113/jp273255
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发表时间：
2017-04-01
影响因子：
5.5
通讯作者：
Levitan, Irena
中科院分区：
文献类型：
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作者：
Ahn, Sang Joon;Fancher, Ibra S.;Levitan, Irena
已知内向整流钾通道(KIR)对血流敏感，但它们在血流诱导的内皮反应中的作用尚不清楚。这项研究的目的是确定KIR通道在血流诱导的血管扩张中的作用，并对这一过程中KIR信号转导的机制提供初步的见解。首先，我们建立了从小鼠肠系膜动脉分离的原代内皮细胞表达对切应力敏感的功能性Kir2.1通道。然后，利用Kir2.1(+/-)杂合子小鼠模型，我们建立了下调Kir2.1导致切变激活的KIR电流显著减少，并抑制内皮素-1预先收缩的加压肠系膜动脉内皮依赖性血流诱导的血管扩张(FIV)的结果。Kir2.1基因的缺失还会导致eNOS和Akt在血流诱导下的磷酸化丧失，并抑制NO的生成。所有这些效应都被内皮细胞(EC)特异性的Kir2.1过表达所完全挽救。FIV中不依赖KIR的成分可通过阻断钙敏感的K+通道而被取消。Kir2.1对非内皮依赖性和K+诱导的裸露动脉血管扩张无影响。Kir2.1(+/-)小鼠还表现出通过颈动脉插管测量的平均血压增加，以及使用尾袖测量的微血管阻力增加。重要的是，阻断KIR通道还可以抑制人体皮下脂肪微血管的血流诱导的血管扩张。内皮KIR通道通过NO依赖机制参与小鼠肠系膜动脉的FIV，而钙敏感K+通道通过NO非依赖途径介导FIV。Kir2通道还调节血管阻力和血压。最后，KIR通道也有助于人体皮下微血管的FIV。
Inwardly rectifying K+ (Kir) channels are known to be sensitive to flow, but their role in flow-induced endothelial responses is not known. The goal of this study is to establish the role of Kir channels in flow-induced vasodilatation and to provide first insights into the mechanisms responsible for Kir signalling in this process. First, we establish that primary endothelial cells isolated from murine mesenteric arteries express functional Kir2.1 channels sensitive to shear stress. Then, using the Kir2.1(+/-) heterozygous mouse model, we establish that downregulation of Kir2.1 results in significant decrease in shear-activated Kir currents and inhibition of endothelium-dependent flow-induced vasodilatation (FIV) assayed in pressurized mesenteric arteries pre-constricted with endothelin-1. Deficiency in Kir2.1 also results in the loss of flow-induced phosphorylation of eNOS and Akt, as well as inhibition of NO generation. All the effects are fully rescued by endothelial cell (EC)-specific overexpression of Kir2.1. A component of FIV that is Kir independent is abrogated by blocking Ca2+-sensitive K+ channels. Kir2.1 has no effect on endothelium-independent and K+-induced vasodilatation in denuded arteries. Kir2.1(+/-) mice also show increased mean blood pressure measured by carotid artery cannulation and increased microvascular resistance measured using a tail-cuff. Importantly, blocking Kir channels also inhibits flow-induced vasodilatation in human subcutaneous adipose microvessels. Endothelial Kir channels contribute to FIV of mouse mesenteric arteries via an NO-dependent mechanism, whereas Ca2+-sensitive K+ channels mediate FIV via an NO-independent pathway. Kir2 channels also regulate vascular resistance and blood pressure. Finally, Kir channels also contribute to FIV in human subcutaneous microvessels.