Metabolic Regulation of Pulmonary Vascular Remodeling

慢性肺病或高血压性肺泡低氧患者发生肺动脉高压 高空暴露。这些疾病影响了大量的患者，并导致了低氧引起的肺血管 重塑是引起肺动脉高压(PH)的最常见原因。我们认为，重塑是由 通过线粒体O2感受器启动血管平滑肌中的氧化还原信号，从而促进细胞 收缩、生长和扩散。我们之前的工作表明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物种(ROS)信号 细胞(PASMC)。我们现在建议测试这些信号是否也驱动血管重塑和代谢 在PASMC中重新编程，导致慢性缺氧期间的PH。ROS在PH中的作用一直很高 因此，这些研究对于澄清这一问题至关重要。慢性低氧激活氧化还原 信号转导和诱导肺血管细胞缺氧诱导因子(HIF-1和HIF-2)。这促进了 代谢重编程朝向糖酵解而不是线粒体氧化磷酸化。我们将测试 这种重新编程是否促进血管重塑和PH。低氧和ROS也激活AMP- 依赖蛋白激酶(AMPK)，一种细胞能量感受器，激活分解代谢途径并抑制 合成代谢，潜在地与重塑反应相反。我们将确定AMPK激活是否 可以限制PASMC的生长、增殖和代谢重编程，从而反对PASMC的发展 pH值为了实现这些目标，我们组装了一套强大的工具来量化和修改氧化还原信号和 代谢途径，这将应用于遗传性肺高压小鼠模型和肺血管细胞。 有肺动脉高压的患者。这些研究将为调控的机制提供新的见解。 慢性低氧引起的重塑和PH，并将确定潜在的治疗靶点 人类低氧相关性肺高压的治疗。

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.