Metabolic Regulation of Pulmonary Vascular Remodeling

肺动脉高压发生于慢性肺部疾病或高血压引起的肺泡缺氧患者。 高空暴露这些疾病影响了大量的患者，缺氧引起的肺血管 重构是肺动脉高压（PH）的最常见原因。我们认为重塑是由 通过线粒体O2传感器启动血管平滑肌中的氧化还原信号，从而促进细胞 收缩、生长和增殖。我们先前的工作暗示线粒体是活性氧的来源 激活肺动脉平滑肌对急性缺氧的功能反应的活性氧（ROS）信号 细胞（PASMC）。我们现在提出测试这些信号是否也驱动血管重塑和代谢 PASMC中的重编程，导致慢性缺氧期间的PH。ROS在PH中的作用一直很高， 这是一个有争议的问题，因此这些研究对于澄清这个问题至关重要。慢性缺氧激活氧化还原 信号传导并诱导肺血管细胞中的缺氧诱导因子（HIF-1和HIF-2）。这促进 代谢重编程朝向糖酵解和远离线粒体氧化磷酸化。我们将测试 这种重编程是否会促进血管重塑和PH。缺氧和ROS也会激活AMP， 依赖性蛋白激酶（AMPK），一种细胞能量传感器，可激活分解代谢途径并抑制 合成代谢，可能对抗重塑反应。我们将确定AMPK激活 可以限制PASMC的生长、增殖和代谢重编程，从而对抗PASMC的发展。 博士为了实现这些目标，我们已经组装了一套强大的工具来量化和修改氧化还原信号， 代谢途径，这将适用于遗传小鼠模型的PH和肺血管细胞， 肺动脉高压患者。这些研究将提供新的见解调节机制， 重塑和PH值的增加，并将确定潜在的治疗目标， 治疗人类缺氧相关PH。

Pulmonary hypertension develops in patients with alveolar hypoxia arising from chronic lung diseases or high altitude exposure. These diseases affect large numbers of patients, and hypoxia-induced pulmonary vascular remodeling is the most common cause of pulmonary hypertension (PH). We propose that remodeling is triggered by mitochondrial O2 sensors that initiate redox signaling in vascular smooth muscle, thereby promoting cell contraction, growth and proliferation. Our previous work implicates mitochondria as a source of reactive oxygen species (ROS) signals that activate functional responses to acute hypoxia in pulmonary artery smooth muscle cells (PASMC). We now propose to test whether these signals also drive vascular remodeling and metabolic reprogramming in PASMC, leading to PH during chronic hypoxia. The role of ROS in PH has been highly controversial, so these studies are critically important for clarifying this issue. Chronic hypoxia activates redox signaling and induces Hypoxia-Inducible Factors (HIF-1 and HIF-2) in pulmonary vascular cells. This promotes metabolic reprogramming toward glycolysis and away from mitochondrial oxidative phosphorylation. We will test whether this reprogramming promotes vascular remodeling and PH. Hypoxia and ROS also activate AMP- dependent Protein Kinase (AMPK), a cellular energy sensor that activates catabolic pathways and inhibits anabolic metabolism, potentially opposing the remodeling response. We will determine whether AMPK activation can limit the growth, proliferation and metabolic reprogramming of PASMC, thereby opposing the development of PH. To achieve these aims we have assembled a powerful set of tools to quantify and modify redox signaling and metabolic pathways, which will be applied in genetic mouse models of PH and in pulmonary vascular cells from patients with pulmonary hypertension. These studies will provide novel insight into the mechanisms regulating the remodeling and PH arising in response to chronic hypoxia, and will identify potential therapeutic targets for the treatment of hypoxia-associated PH in humans.