Endothelial-dependent dilation following chronic hypoxia involves TRPV4-mediated activation of endothelial BK channels.
Endothelial-dependent dilation following chronic hypoxia involves TRPV4-mediated activation of endothelial BK channels.
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DOI：
10.1007/s00424-018-2112-5
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Walker BR
中科院分区：
文献类型：
--
作者：
Naik JS;Walker BR
慢性缺氧（CH）后，由于内皮依赖性超极化（EDH），全身血管系统表现出钝性血管收缩。先前的数据表明，CH之后，EDH介导的血管舒张从依赖于SKca和IKca通道转换为内皮BKca通道（eBK）的激活。CH后内皮细胞刺激激活eBK通道的机制尚不清楚。我们假设CH后，EDH依赖性血管舒张涉及TRPV 4依赖性eBK通道激活。ACh诱导的浓度依赖性扩张加压股薄动脉从常氧和CH大鼠。抑制TRPV 4（RN-1734）减弱了CH大鼠动脉中的ACh反应，但对常氧动物没有影响。在L-NNA和吲哚美辛的存在下，TRPV 4阻断减弱了CH大鼠动脉中ACh诱导的血管舒张。ACh引起两组动脉内皮TRPV 4介导的Ca 2+事件。GSK 1016790 A（GSK 101，TRPV 4激动剂）在含氧量正常和CH大鼠的动脉中引起血管舒张。在含氧量正常的动物的动脉中，TRAM-34/蜂毒肽消除了对TRPV 4激活的扩张，而管腔伊比利亚毒素没有影响。在CH大鼠中，仅给予所有三种Kca通道抑制剂即可消除TRPV 4激活的扩张。使用Duolink®，我们观察到股薄肌动脉和RAEC中Cav-1、TRPV 4和BK通道之间的共定位。用甲基-β-环糊精破坏内皮小窝可显著降低ACh诱导的两组动脉血管舒张作用。在股薄动脉，内皮细胞膜胆固醇显着降低48小时后的CH。总之，CH结果在毒蕈碱受体，TRPV 4和KCa通道之间的功能耦合在股薄动脉。
Following chronic hypoxia (CH), the systemic vasculature exhibits blunted vasoconstriction due to endothelial-dependent hyperpolarization (EDH). Previous data demonstrate that subsequent to CH, EDH-mediated vasodilation switches from a reliance on SKca and IKca channels to activation of the endothelial BKca channels (eBK). The mechanism by which endothelial cell stimulation activates eBK channels following CH is not known. We hypothesized that following CH, EDH-dependent vasodilation involves a TRPV4-dependent activation of eBK channels. ACh induced concentration-dependent dilation in pressurized gracilis arteries from both normoxic and CH rats. Inhibition of TRPV4 (RN-1734) attenuated the ACh response in arteries from CH rats but had no effect in normoxic animals. In the presence of L-NNA and indomethacin, TRPV4 blockade attenuated ACh-induced vasodilation in arteries from CH rats. ACh elicited endothelial TRPV4-mediated Ca2+ events in arteries from both groups. GSK1016790A (GSK101, TRPV4 agonist) elicited vasodilation in arteries from normoxic and CH rats. In arteries from normoxic animals, TRAM-34/apamin abolished the dilation to TRPV4 activation, whereas luminal iberiotoxin had no effect. In CH rats, only administration of all three Kca channel inhibitors abolished the dilation to TRPV4 activation. Using Duolink®, we observed co-localization between Cav-1, TRPV4, and BK channels in gracilis arteries and in RAECs. Disruption of endothelial caveolae with methyl-β-cyclodextrin significantly decreased ACh-induced vasodilation in arteries from both groups. In gracilis arteries, endothelial membrane cholesterol was significantly decreased following 48 h of CH. In conclusion, CH results in a functional coupling between muscarinic receptors, TRPV4 and Kca channels in gracilis arteries.
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