Mooers Emily A, Johnson Hollis M, Michalkiewicz Teresa, Rana Ujala, Joshi Chintamani, Afolayan Adeleye J, Teng Ru-Jeng, Konduri Girija G
Institutional Affiliation (of all authors): Department of Pediatrics, Division of Neonatology, Medical College of Wisconsin (MCW), Milwaukee, WI, USA.
Pediatr Res. 2024 Dec;96(7):1636-1644. doi: 10.1038/s41390-024-03223-2. Epub 2024 Jun 6.
Persistent Pulmonary Hypertension of the Newborn (PPHN) is characterized by elevated pulmonary vascular resistance (PVR), resulting in hypoxemia. Impaired angiogenesis contributes to high PVR. Pulmonary artery endothelial cells (PAECs) in PPHN exhibit decreased mitochondrial respiration and angiogenesis. We hypothesize that Peroxisome Proliferator-Activated Receptor Gamma Co-Activator-1α (PGC-1α) downregulation leads to reduced mitochondrial function and angiogenesis in PPHN.
Studies were performed in PAECs isolated from fetal lambs with PPHN induced by ductus arteriosus constriction, with gestation-matched controls and in normal human umbilical vein endothelial cells (HUVECs). PGC-1α was knocked downed in control lamb PAECs and HUVECs and overexpressed in PPHN PAECs to investigate the effects on mitochondrial function and angiogenesis.
PPHN PAECs had decreased PGC-1α expression compared to controls. PGC-1α knockdown in HUVECs led to reduced Nuclear Respiratory Factor-1 (NRF-1), Transcription Factor-A of Mitochondria (TFAM), and mitochondrial electron transport chain (ETC) complexes expression. PGC-1α knockdown in control PAECs led to decreased in vitro capillary tube formation, cell migration, and proliferation. PGC-1α upregulation in PPHN PAECs led to increased ETC complexes expression and improved tube formation, cell migration, and proliferation.
PGC-1α downregulation contributes to reduced mitochondrial oxidative phosphorylation through control of the ETC complexes, thereby affecting angiogenesis in PPHN.
Reveals a novel mechanism for angiogenesis dysfunction in persistent pulmonary hypertension of the newborn (PPHN). Identifies a key mitochondrial transcription factor, Peroxisome Proliferator-Activated Receptor Gamma Co-Activator-1α (PGC-1α), as contributing to the altered adaptation and impaired angiogenesis function that characterizes PPHN through its regulation of mitochondrial function and oxidative phosphorylation. May provide translational significance as this mechanism offers a new therapeutic target in PPHN, and efforts to restore PGC-1α expression may improve postnatal transition in PPHN.
新生儿持续性肺动脉高压（PPHN）的特征是肺血管阻力（PVR）升高，导致低氧血症。血管生成受损会导致高PVR。PPHN中的肺动脉内皮细胞（PAECs）表现出线粒体呼吸和血管生成减少。我们假设过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）下调会导致PPHN中线粒体功能和血管生成减少。
对从经动脉导管缩窄诱导的PPHN胎羊分离的PAECs进行研究，设妊娠匹配的对照组，并以正常人脐静脉内皮细胞（HUVECs）作为对照。在对照羔羊PAECs和HUVECs中敲低PGC-1α，并在PPHN PAECs中过表达，以研究其对线粒体功能和血管生成的影响。
与对照组相比，PPHN PAECs的PGC-1α表达降低。HUVECs中PGC-1α敲低导致核呼吸因子-1（NRF-1）、线粒体转录因子A（TFAM）和线粒体电子传递链（ETC）复合物表达减少。对照PAECs中PGC-1α敲低导致体外毛细血管管形成、细胞迁移和增殖减少。PPHN PAECs中PGC-1α上调导致ETC复合物表达增加，并改善管形成、细胞迁移和增殖。
PGC-1α下调通过控制ETC复合物导致线粒体氧化磷酸化减少，从而影响PPHN中的血管生成。
揭示了新生儿持续性肺动脉高压（PPHN）中血管生成功能障碍的新机制。确定了一个关键的线粒体转录因子，即过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α），它通过调节线粒体功能和氧化磷酸化，导致PPHN中适应性改变和血管生成功能受损。这一机制可能具有转化意义，因为它为PPHN提供了一个新的治疗靶点，恢复PGC-1α表达的努力可能会改善PPHN的出生后过渡。
