Myoendothelial coupling through Cx40 contributes to EDH-induced vasodilation in murine renal arteries: evidence from experiments and modelling
Myoendothelial coupling through Cx40 contributes to EDH-induced vasodilation in murine renal arteries: evidence from experiments and modelling
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DOI：
10.1111/apha.12906
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发表时间：
2018-01-01
影响因子：
6.3
通讯作者：
Sorensen, C. M.
中科院分区：
文献类型：
--
作者：
Brasen, J. C.;de Wit, C.;Sorensen, C. M.
肾血管阻力的调节在控制动脉血压中起主要作用。内皮细胞参与了这一调节，因为内皮源性超极化在较小的肾动脉和小动脉中起着重要作用，但确切的机制仍不清楚。我们评估了钙激活的小（SK）和中等（IK）电导钾通道的作用。评价了内向整流钾通道（Kir）和Na+/K+-ATP酶的作用以及间隙连接的贡献。数学模型估计的离子扩散和电耦合在肌内皮细胞间隙连接被用来解释result.ResultsLack的连接蛋白40显着降低肾内皮细胞超极化。抑制SK和IK通道显着衰减肾EDH在野生型和敲除小鼠相似的程度。抑制Kir和Na+/K+-ATP酶影响野生型和基因敲除小鼠的反应，但在不同水平的刺激。该模型证实，内皮SK和IK通道的激活产生进入血管平滑肌细胞的超极化电流。此外，细胞外钾增加足以激活Kir和Na+/K+-ATPases. Conclusion肾内皮细胞超极化主要是由激活IK和SK通道。该模型表明，超极化可以通过肌内皮间隙连接传播，但释放足够的钾来激活Kir和Na+/K+-ATP酶。减少耦合似乎转向钾的释放信号通路。然而，也存在一种替代途径，需要加以研究。
Regulation of renal vascular resistance plays a major role in controlling arterial blood pressure. The endothelium participates in this regulation as endothelial derived hyperpolarization plays a significant role in smaller renal arteries and arterioles, but the exact mechanisms are still unknown.AimTo investigate the role of vascular gap junctions and potassium channels in the renal endothelial derived hyperpolarization.MethodsIn interlobar arteries from wild-type and connexin40 knockout mice, we assessed the role of calcium-activated small (SK) and intermediate (IK) conductance potassium channels. The role of inward rectifier potassium channels (Kir) and Na+/K+-ATPases was evaluated as was the contribution from gap junctions. Mathematical models estimating diffusion of ions and electrical coupling in myoendothelial gap junctions were used to interpret the results.ResultsLack of connexin40 significantly reduces renal endothelial hyperpolarization. Inhibition of SK and IK channels significantly attenuated renal EDH to a similar degree in wild-type and knockout mice. Inhibition of Kir and Na+/K+-ATPases affected the response in wild-type and knockout mice but at different levels of stimulation. The model confirms that activation of endothelial SK and IK channels generates a hyperpolarizing current that enters the vascular smooth muscle cells. Also, extracellular potassium increases sufficiently to activate Kir and Na+/K+-ATPases.ConclusionRenal endothelial hyperpolarization is mainly initiated by activation of IK and SK channels. The model shows that hyperpolarization can spread through myoendothelial gap junctions but enough potassium is released to activate Kir and Na+/K+-ATPases. Reduced coupling seems to shift the signalling pathway towards release of potassium. However, an alternative pathway also exists and needs to be investigated.