John Curtin School of Medical Research, Australian National University, Canberra ACT 0200, Australia.
J Physiol. 2013 Apr 15;591(8):2157-73. doi: 10.1113/jphysiol.2013.250928. Epub 2013 Feb 25.
Regulation of blood flow in microcirculatory networks depends on spread of local vasodilatation to encompass upstream arteries; a process mediated by endothelial conduction of hyperpolarization. Given that endothelial coupling is reduced in hypertension, we used hypertensive Cx40ko mice, in which endothelial coupling is attenuated, to investigate the contribution of the renin-angiotensin system and reduced endothelial cell coupling to conducted vasodilatation of cremaster arterioles in vivo. When the endothelium was disrupted by light dye treatment, conducted vasodilatation, following ionophoresis of acetylcholine, was abolished beyond the site of endothelial damage. In the absence of Cx40, sparse immunohistochemical staining was found for Cx37 in the endothelium, and endothelial, myoendothelial and smooth muscle gap junctions were identified by electron microscopy. Hyperpolarization decayed more rapidly in arterioles from Cx40ko than wild-type mice. This was accompanied by a shift in the threshold potential defining the linear relationship between voltage and diameter, increased T-type calcium channel expression and increased contribution of T-type (3 μmol l(-1) NNC 55-0396), relative to L-type (1 μmol l(-1) nifedipine), channels to vascular tone. The change in electromechanical coupling was reversed by inhibition of the renin-angiotensin system (candesartan, 1.0 mg kg(-1) day(-1) for 2 weeks) or by acute treatment with the superoxide scavenger tempol (1 mmol l(-1)). Candesartan and tempol treatments also significantly improved conducted vasodilatation. We conclude that conducted vasodilatation in Cx40ko mice requires the endothelium, and attenuation results from both a reduction in endothelial coupling and an angiotensin II-induced increase in oxidative stress. We suggest that during cardiovascular disease, the ability of microvascular networks to maintain tissue integrity may be compromised due to oxidative stress-induced changes in electromechanical coupling.
微循环网络中的血流调节依赖于局部血管舒张的传播，以包含上游动脉；这个过程是由内皮细胞超极化的传导介导的。由于高血压患者内皮细胞偶联减少，我们使用高血压 Cx40ko 小鼠（内皮细胞偶联减弱），研究肾素-血管紧张素系统和内皮细胞偶联减少对活体提睾肌小动脉传导性血管舒张的贡献。当用光染料处理破坏内皮细胞时，在内皮损伤部位之外，乙酰胆碱离子载体转染后，传导性血管舒张被消除。在没有 Cx40 的情况下，内皮中稀疏的 Cx37 免疫组织化学染色，电子显微镜鉴定内皮、肌内皮和平滑肌缝隙连接。与野生型小鼠相比，Cx40ko 小鼠的血管超极化衰减更快。这伴随着阈值电位的变化，该电位定义了电压和直径之间的线性关系，T 型钙通道表达增加，以及 T 型（3 μmol l(-1) NNC 55-0396）相对 L 型（1 μmol l(-1)硝苯地平）通道对血管张力的贡献增加。电机械偶联的变化可以通过抑制肾素-血管紧张素系统（坎地沙坦，1.0 mg kg(-1) 天(-1)，持续 2 周）或急性使用超氧化物清除剂 tempol（1 mmol l(-1)）逆转。坎地沙坦和 tempol 治疗也显著改善了传导性血管舒张。我们得出结论，Cx40ko 小鼠的传导性血管舒张需要内皮细胞，并且衰减是由于内皮细胞偶联减少和血管紧张素 II 诱导的氧化应激增加所致。我们认为，在心血管疾病中，由于氧化应激诱导的电机械偶联变化，微血管网络维持组织完整性的能力可能受到损害。
