Redox Regulation of Vascular cGMP Signaling in Neonatal Lungs

总结 支气管肺发育不良（BPD）是早产的常见并发症，影响30%的婴儿， 出生体重< 1000克。近年来，肺动脉高压（PH）和右心室肥厚（RVH） 在大约25%的中度或重度BPD婴儿中被认为是并发症。一旦 婴儿发生PH，关于如何治疗他们知之甚少，并且发病率和死亡率的风险非常高。一 BPD治疗的主要支柱是氧气（O2），但超生理O2浓度与 机械通气增加活性氧（ROS）的产生，诱导显著的血管 新生儿功能障碍。ROS介导的肺血管失调的潜在关键靶点 参与cGMP信号传导-可溶性鸟苷酸环化酶（sGC）和磷酸二酯酶5（PDE 5）。在 在上一个资助期，我们利用高氧诱导的肺病和PH的小鼠模型来证明 暴露于高氧的小鼠发生显著的肺和血管疾病，其特征在于肺泡 简化、毛细血管减少、小肺动脉（PA）重塑和RVH。我们证明了 高氧迅速降低肺和PA可溶性鸟苷酸环化酶（sGC）的表达和活性， 肺和PA磷酸二酯酶5（PDE 5）活性增加，导致cGMP介导的 下行信号。给予低剂量西地那非（一种PDE 5抑制剂）同时预防高氧 增加PDE 5活性、血管重塑和RVH，但无法恢复正常毛细血管密度 和肺泡化。在这项提案的初步数据中，我们已经证明了另一种环境 压力源，由于胎盘功能不全引起的宫内生长受限（IUGR），导致 肺泡化，关键的肺生长因子胰岛素样生长因子-1（IGF-1）的表达降低， sGC表达和活性降低，肺泡化受损。IUGR小鼠有一个夸大的 高氧表型与sGC表达和活性进一步降低的适当生长小鼠 和肺泡化受损我们假设生长受限和高氧诱导的 线粒体ROS破坏关键的sGC-cGMP信号通路，导致受损的 肺泡化和血管生成。我们将利用我们建立的高氧诱导肺的小鼠模型， 损伤与IUGR的新模型相结合，以阐明ROS和 生长限制破坏sGC-cGMP信号传导和肺发育。这些研究将提供 病理生理学，机制框架，以改善药物治疗的BPD婴儿与PH。我们 我相信sGC是影响新生儿肺泡化和血管生成的多种信号的关键整合者 期sGC刺激剂如riocinguat已被批准用于PH成人，代表了一种新的 BPD-PH婴儿的潜在直接治疗选择，如果可以证明其使用的合理性。

SUMMARY Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth affecting 30% of infants with birthweights < 1000 grams. Recently, pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) have been recognized as complications in approximately 25% of infants with moderate or severe BPD. Once infants develop PH, little is known about how to treat them, and risk of morbidity and mortality is very high. One of the mainstays of BPD therapy is oxygen (O2), but supraphysiologic O2 concentrations in combination with mechanical ventilation increase reactive oxygen species (ROS) production, inducing significant vascular dysfunction in neonates. Potential key targets for ROS-mediated dysregulation in the pulmonary vasculature are involved in cGMP signaling - soluble guanylate cyclase (sGC) and phosphodiesterase 5 (PDE5). In the previous funding period, we utilized a mouse model of hyperoxia-induced lung disease and PH to demonstrate that hyperoxia-exposed mice develop significant pulmonary and vascular disease, characterized by alveolar simplification, fewer capillaries, small pulmonary arteries (PA) remodeling, and RVH. We demonstrated that hyperoxia rapidly decreased lung and PA soluble guanylate cyclase (sGC) expression and activity and increased lung and PA phosphodiesterase 5 (PDE5) activity, leading to disruption of cGMP-mediated downstream signaling. Giving low-dose sildenafil, a PDE5 inhibitor, concurrent with hyperoxia prevented increased PDE5 activity, vascular remodeling, and RVH, but was unable to restore normal capillary density and alveolarization. In preliminary data for this proposal, we have demonstrated that another environmental stressor, intrauterine growth restriction (IUGR) due to placental insufficiency, leads to a significant delay in alveolarization with decreased expression of a key lung growth factor, insulin-like growth factor-1 (IGF-1), decreased sGC expression and activity, and impaired alveolarization. IUGR mice have an exaggerated phenotype with hyperoxia vs. appropriately grown mice with further decreased sGC expression and activity and impaired alveolarization. We hypothesize that both growth restriction and hyperoxia-induced mitochondrial ROS disrupt the critical sGC-cGMP signaling pathway, leading to impaired alveolarization and angiogenesis. We will utilize our established mouse model of hyperoxia-induced lung injury in combination with a novel model of IUGR to elucidate the molecular mechanism by which ROS and growth restriction disrupt sGC-cGMP signaling and lung development. These studies will provide the pathophysiologic, mechanistic framework to improve pharmacologic treatment of BPD infants with PH. We believe sGC is a key integrator for multiple signals that impact alveolarization and angiogenesis in the neonatal period. sGC stimulators such as riocinguat are approved in adults with PH and represent a novel and potentially immediate therapeutic option for BPD-PH infants if a rationale for their use can be demonstrated.