From the Department of Anesthesiology and Center for Excellence in Cardiovascular Research, Texas Tech University Health Sciences Center, Lubbock.
Hypertension. 2015 Jan;65(1):130-9. doi: 10.1161/HYPERTENSIONAHA.114.04473. Epub 2014 Oct 13.
Vascular thiol redox state has been shown to modulate vasodilator functions in large conductance Ca2+ -activated K+ channels and other related channels. However, the role of vascular redox in small resistance arteries is unknown. To determine how in vivo modulation of thiol redox state affects small resistance arteries relaxation, we generated a transgenic mouse strain that overexpresses thioredoxin, a small redox protein (Trx-Tg), and another strain that is thioredoxin-deficient (dnTrx-Tg). The redox state of the mesenteric arteries (MAs) in Trx-Tg mice is found to be predominantly in reduced state; in contrast, MAs from dnTrx-Tg mice remain in oxidized state. Thus, we created an in vivo redox system of mice and isolated the second-order branches of the main superior MAs from wild-type, Trx-Tg, or dnTrx-Tg mice to assess endothelium-dependent relaxing responses in a wire myograph. In MAs isolated from Trx-Tg mice, we observed an enhanced intermediate-conductance Ca2+ -activated potassium channel contribution resulting in a larger endothelium-dependent hyperpolarizing (EDH) relaxation in response to indirect (acetylcholine) and direct (NS309) opening of endothelial calcium-activated potassium channels. MAs derived from dnTrx-Tg mice showed both blunted nitric oxide-mediated and EDH-mediated relaxation compared with Trx-Tg mice. In a control study, diamide decreased EDH relaxations in MAs of wild-type mice, whereas dithiothreitol improved EDH relaxations and was able to restore the diamide-induced impairment in EDH response. Furthermore, the basal or angiotensin II-mediated systolic blood pressure remained significantly lower in Trx-Tg mice compared with wild-type or dnTrx-Tg mice, thus directly establishing redox-mediated EDH in blood pressure control.
血管硫醇氧化还原状态已被证明可调节大电导钙激活钾通道和其他相关通道的血管舒张功能。然而，血管氧化还原在小阻力动脉中的作用尚不清楚。为了确定体内硫醇氧化还原状态的调节如何影响小阻力动脉的松弛，我们生成了一种过表达硫氧还蛋白（Trx-Tg）的转基因小鼠品系和一种硫氧还蛋白缺乏（dnTrx-Tg）的另一种品系。发现 Trx-Tg 小鼠肠系膜动脉（MAs）的氧化还原状态主要处于还原状态；相比之下，dnTrx-Tg 小鼠的 MAs 仍处于氧化状态。因此，我们创建了一种体内氧化还原系统，并从野生型、Trx-Tg 或 dnTrx-Tg 小鼠中分离出主要 superior MAs 的二级分支，以在wire myograph 中评估内皮依赖性舒张反应。在 Trx-Tg 小鼠分离的 MAs 中，我们观察到中间电导钙激活钾通道的贡献增强，导致间接（乙酰胆碱）和直接（NS309）开放内皮钙激活钾通道时，内皮依赖性超极化（EDH）松弛更大。与 Trx-Tg 小鼠相比，dnTrx-Tg 小鼠的 MAs 显示出一氧化氮介导的和 EDH 介导的松弛均减弱。在对照研究中，二酰胺降低了野生型小鼠 MAs 的 EDH 松弛，而二硫苏糖醇改善了 EDH 松弛，并能够恢复二酰胺诱导的 EDH 反应损伤。此外，Trx-Tg 小鼠的基础或血管紧张素 II 介导的收缩压明显低于野生型或 dnTrx-Tg 小鼠，因此直接确立了氧化还原介导的 EDH 在血压控制中的作用。
