Aberrant PGC-1α signaling in a lamb model of persistent pulmonary hypertension of the newborn. Pediatr Res 2024 Dec;96(7):1636-1644
Date
06/07/2024Pubmed ID
38844539Pubmed Central ID
PMC12101728DOI
10.1038/s41390-024-03223-2Scopus ID
2-s2.0-85195582134 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: PGC-1α downregulation contributes to reduced mitochondrial oxidative phosphorylation through control of the ETC complexes, thereby affecting angiogenesis in PPHN.
IMPACT: 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.
Author List
Mooers EA, Johnson HM, Michalkiewicz T, Rana U, Joshi C, Afolayan AJ, Teng RJ, Konduri GGAuthors
Adeleye James Afolayan MBBS Associate Professor in the Pediatrics department at Medical College of WisconsinHollis M. Johnson Instructor II in the Pediatrics department at Medical College of Wisconsin
Girija Ganesh Konduri MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Emily A. Mooers MD Assistant Professor in the Pediatrics department at Medical College of Wisconsin
Ru-Jeng Teng MD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Newborn
Cell Movement
Cells, Cultured
Disease Models, Animal
Endothelial Cells
Human Umbilical Vein Endothelial Cells
Humans
Infant, Newborn
Mitochondria
Neovascularization, Pathologic
Neovascularization, Physiologic
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Persistent Fetal Circulation Syndrome
Pulmonary Artery
Sheep
Signal Transduction
