Morton Susan K, Chaston Daniel J, Howitt Lauren, Heisler Jillian, Nicholson Bruce J, Fairweather Stephen, Bröer Stefan, Ashton Anthony W, Matthaei Klaus I, Hill Caryl E
From the Eccles Institute of Neuroscience (S.K.M, D.J.C., L.H., C.E.H.) and Department of Molecular Bioscience (K.I.M.), The John Curtin School of Medical Research and Division of Biomedical Science and Biochemistry, Research School of Biology (S.F., S.B.), The Australian National University, Canberra, Australia; Department of Biochemistry, University of Texas Health Sciences Centre, San Antonio, Texas (J.H., B.J.N.); and Division of Perinatal Research, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, Australia (A.W.A.).
Hypertension. 2015 Mar;65(3):662-9. doi: 10.1161/HYPERTENSIONAHA.114.04578. Epub 2014 Dec 29.
During activity, coordinated vasodilation of microcirculatory networks with upstream supply vessels increases blood flow to skeletal and cardiac muscles and reduces peripheral resistance. Endothelial dysfunction in humans attenuates activity-dependent vasodilation, resulting in exercise-induced hypertension in otherwise normotensive individuals. Underpinning activity-dependent hyperemia is an ascending vasodilation in which the endothelial gap junction protein, connexin (Cx)40, plays an essential role. Because exercise-induced hypertension is proposed as a forerunner to clinical hypertension, we hypothesized that endothelial disruption of Cx40 function in mice may create an animal model of this condition. To this end, we created mice in which a mutant Cx40T152A was expressed alongside wildtype Cx40 selectively in the endothelium. Expression of the Cx40T152A transgene in Xenopus oocytes and mouse coronary endothelial cells in vitro impaired both electric and chemical conductance and acted as a dominant-negative against wildtype Cx40, Cx43, and Cx45, but not Cx37. Endothelial expression of Cx40T152A in Cx40T152ATg mice attenuated ascending vasodilation, without effect on radial coupling through myoendothelial gap junctions. Using radiotelemetry, Cx40T152ATg mice showed an activity-dependent increase in blood pressure, which was significantly greater than in wildtype mice, but significantly less than in chronically hypertensive, Cx40knockout mice. The increase in heart rate with activity was also greater than in wildtype or Cx40knockout mice. We conclude that the endothelial Cx40T152A mutation attenuates activity-dependent vasodilation, producing a model of exercise-induced hypertension. These data highlight the importance of endothelial coupling through Cx40 in regulating blood pressure during activity.
在活动期间，微循环网络与上游供应血管的协调性血管舒张增加了流向骨骼肌和心肌的血流量，并降低了外周阻力。人类的内皮功能障碍会减弱活动依赖性血管舒张，导致原本血压正常的个体出现运动性高血压。活动依赖性充血的基础是一种上行性血管舒张，其中内皮间隙连接蛋白连接蛋白（Cx）40起着至关重要的作用。由于运动性高血压被认为是临床高血压的先兆，我们假设小鼠中Cx40功能的内皮破坏可能会创建这种病症的动物模型。为此，我们创建了在内皮中选择性地与野生型Cx40一起表达突变型Cx40T152A的小鼠。Cx40T152A转基因在非洲爪蟾卵母细胞和小鼠冠状动脉内皮细胞中的体外表达损害了电传导和化学传导，并对野生型Cx40、Cx43和Cx45起显性负性作用，但对Cx37没有作用。Cx40T152A在Cx40T152ATg小鼠中的内皮表达减弱了上行性血管舒张，而对通过肌内皮间隙连接的径向耦合没有影响。使用无线电遥测技术，Cx40T152ATg小鼠显示出活动依赖性血压升高，这明显高于野生型小鼠，但明显低于慢性高血压的Cx40基因敲除小鼠。活动时心率的增加也高于野生型或Cx40基因敲除小鼠。我们得出结论，内皮Cx40T152A突变减弱了活动依赖性血管舒张，产生了运动性高血压模型。这些数据突出了通过Cx40进行内皮耦合在活动期间调节血压的重要性。
