Department of Pediatrics, Maastricht University Medical Center (MUMC+), School for Oncology and Developmental Biology (GROW), Maastricht, the Netherlands.
Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES), Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
Free Radic Biol Med. 2019 Oct;142:82-96. doi: 10.1016/j.freeradbiomed.2019.04.008. Epub 2019 Apr 14.
Reactive oxygen species (ROS) are frequently seen as pathological agents of oxidative stress. However, ROS are not always deleterious and can also act as cell signaling molecules. Vascular oxygen sensing and signaling during fetal-to-neonatal circulatory transition is a remarkable example of the physiological regulatory actions of ROS. The fetal relative hypoxic environment induces hypoxic pulmonary vasoconstriction (HPV) and ductus arteriosus (DA) relaxation favoring the presence of high pulmonary vascular resistance and right-to-left ductal shunt. At birth, the increase in oxygen tension causes relaxation of pulmonary arteries (PAs) and normoxic DA vasoconstriction (NDAV), thus diverting blood flow to the lungs. Although the response to changes in oxygen tension is diametrically opposite, the mechanisms responsible for HPV and NDAV appear to be the result of a similar interaction between triggering and modulating factors that lead to an increase in cytosolic Ca concentration and Ca sensitization of the contractile apparatus. Growing evidence points to an increase in ROS (mitochondria- and/or NADPH-derived superoxide and/or HO), leading to inhibition of voltage-gated K channels, membrane depolarization, and activation of voltage-gated L-type Ca channels as critical events in the signaling pathway of both HPV and NDAV. Several groups of investigators have completed this pathway adding other elements such as neutral sphingomyelinase-derived ceramide, the sarcoplasmic/endoplasmic reticulum (through ryanodine and inositol 1,4,5-trisphosphate receptors), Rho kinase-mediated Ca sensitization, or transient receptor potential channels. The present review focus on the role of ROS as mediators of the homeostatic oxygen sensing system during fetal and neonatal life not only in the PAs and DA but also in systemic arteries.
活性氧（ROS）通常被视为氧化应激的病理性致病因子。然而，ROS 并不总是有害的，也可以作为细胞信号分子发挥作用。胎儿向新生儿循环过渡期间的血管氧感应和信号转导是 ROS 发挥生理调节作用的一个显著例子。胎儿相对缺氧环境诱导低氧性肺血管收缩（HPV）和动脉导管（DA）松弛，有利于维持高肺血管阻力和右向左导管分流。出生时，氧张力的增加导致肺动脉（PAs）和正常氧合 DA 收缩（NDAV）松弛，从而将血流分流至肺部。尽管对氧张力变化的反应是截然相反的，但 HPV 和 NDAV 的机制似乎是触发和调节因素之间类似相互作用的结果，导致细胞溶质 Ca 浓度增加和收缩装置的 Ca 敏化。越来越多的证据表明 ROS（线粒体和/或 NADPH 衍生的超氧阴离子和/或 HO）增加，导致电压门控 K 通道抑制、膜去极化和电压门控 L 型 Ca 通道激活，这是 HPV 和 NDAV 信号通路中的关键事件。一些研究小组已经完成了这个通路，增加了其他元素，如中性鞘磷脂酶衍生的神经酰胺、肌浆/内质网（通过肌醇 1,4,5-三磷酸受体）、Rho 激酶介导的 Ca 敏化或瞬时受体电位通道。本综述重点讨论了 ROS 在胎儿和新生儿生命期间作为稳态氧感应系统的介质的作用，不仅在 PAs 和 DA 中，而且在体循环动脉中也发挥作用。
