Elevated resistance of pulmonary circulation after chronic hypoxia exposure leads to pulmonary hypertension. Contributing to this pathological process is enhanced pulmonary vasoconstriction through both calcium-dependent and calcium sensitization mechanisms. Reactive oxygen species (ROS), as a result of increased enzymatic production and/or decreased scavenging, participate in augmentation of pulmonary arterial constriction by potentiating calcium influx as well as activation of myofilament sensitization, therefore mediating the development of pulmonary hypertension. Here, we review the effects of chronic hypoxia on sources of ROS within the pulmonary vasculature including NADPH oxidases, mitochondria, uncoupled endothelial nitric oxide synthase, xanthine oxidase, monoamine oxidases and dysfunctional superoxide dismutases. We also summarize the ROS-induced functional alterations of various Ca²⁺ and K⁺ channels involved in regulating Ca²⁺ influx, and of Rho kinase that is responsible for myofilament Ca²⁺ sensitivity. A variety of antioxidants have been shown to have beneficial therapeutic effects in animal models of pulmonary hypertension, supporting the role of ROS in the development of pulmonary hypertension. A better understanding of the mechanisms by which ROS enhance vasoconstriction will be useful in evaluating the efficacy of antioxidants for the treatment of pulmonary hypertension.

中文翻译：

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慢性缺氧引起的肺动脉高压的血管收缩机制：氧化信号的作用

慢性缺氧后肺循环阻力升高导致肺动脉高压。通过钙依赖性和钙敏化机制增强的肺血管收缩促成了这一病理过程。由于酶产生增加和/或清除减少，活性氧（ROS）通过增强钙内流以及肌丝敏化的激活参与肺动脉收缩的增强，从而介导肺动脉高压的发展。在此，我们回顾了慢性缺氧对肺血管内 ROS 来源的影响，包括 NADPH 氧化酶、线粒体、未偶联内皮一氧化氮合酶、黄嘌呤氧化酶、单胺氧化酶和功能失调的超氧化物歧化酶。我们还总结了 ROS 诱导的参与调节 Ca ^{2+内流的各种 Ca 2+}和 K ⁺通道以及负责肌丝 Ca ²⁺敏感性的 Rho 激酶的功能改变。多种抗氧化剂已被证明对肺动脉高压动物模型具有有益的治疗作用，支持活性氧在肺动脉高压发展中的作用。更好地了解 ROS 增强血管收缩的机制将有助于评估抗氧化剂治疗肺动脉高压的功效。