Emily A. Mooers, Ujala Rana, Chintamani N. Joshi, Adeleye J. Afolayan, Ru-Jeng Teng, Girija Ganesh Konduri
Medical College of Wisconsin.
United States
American Journal of Physiology Lung Cellular and Molecular Physiology
Am J Physiol Lung Cell Mol Physiol 2026;
DOI: 10.1152/ajplung.00229.2025
Abstract
Pulmonary vascular remodeling contributes to Persistent Pulmonary Hypertension of the Newborn (PPHN); the mechanisms remain unknown. 5’AMP-Activated Protein Kinase (AMPK) is a critical regulator of energy balance and metabolism. We investigated the hypothesis that decreased AMPK function in pulmonary artery smooth muscle cells (PASMCs) leads to impaired mitochondrial capacity to perform oxidative phosphorylation and altered notch ligand expression, which together promote vascular remodeling in PPHN. Studies were performed in fetal lambs with PPHN induced by prenatal ductus arteriosus constriction and gestation-matched controls. For in vitro studies, PPHN PASMCs were treated with AMPK agonists, A769662 or metformin, and compared to untreated control and PPHN PASMCs. Expression of phosphorylated-AMPK (p-AMPK) and its downstream mediators, PGC-1α, mitochondrial electron transport chain (ETC) complexes, differentiation markers, and notch ligands, were assessed using immunoblotting in control and PPHN PASMCs. For in vivo studies, PPHN lambs were treated with metformin, and were compared to untreated control and PPHN lambs. Lung sections from in vivo experiments were evaluated via immunofluorescence. Compared to controls, p-AMPK, PGC-1α and ETC complexes were decreased in PPHN PASMCs and lung sections. PASMC differentiation marker, MYH11, was reduced in PPHN lung sections while dedifferentiation marker, vimentin, was increased. Expression of Jag1 and Hey1 in Notch pathway were reduced in PPHN PASMCs and lung sections. A769662 and metformin increased the expression of PGC-1α, ETC complexes I and IV, Jag1 and Hey1 in PPHN PASMCs. Decreased AMPK function contributes to reduced mitochondrial oxidative phosphorylation capacity, less differentiated PASMCs, and imbalanced notch signaling, promoting remodeling in PPHN.
Category
Class I. Persistent Pulmonary Hypertension of the Newborn
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Medical Therapy. Efficacy or Lack of Efficacy
Pulmonary Vascular Pathology
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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