AMP-Kinase Dysfunction Alters Notch Ligands to Impair Angiogenesis in Neonatal Pulmonary Hypertension. Am J Respir Cell Mol Biol 2020 Jun;62(6):719-731
Date
02/13/2020Pubmed ID
32048878Pubmed Central ID
PMC7258820DOI
10.1165/rcmb.2019-0275OCScopus ID
2-s2.0-85085714904 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
Decreased angiogenesis contributes to persistent pulmonary hypertension of the newborn (PPHN); mechanisms remain unclear. AMPK (5'AMP activated protein kinase) is a key regulator of cell metabolism. We investigated the hypothesis that a decrease in AMPK function leads to mitochondrial dysfunction and altered balance of notch ligands delta-like 4 (DLL4) and Jagged 1 (Jag1) to impair angiogenesis in PPHN. Studies were done in fetal lambs with PPHN induced by prenatal ductus arteriosus constriction and gestation-matched control lambs. PPHN lambs were treated with saline or AMPK agonist metformin. Angiogenesis was assessed in lungs with micro-computed tomography angiography and histology. AMPK function; expression of mitochondrial electron transport chain (ETC) complex proteins I-V, Dll4, and Jag1; mitochondrial number; and in vitro angiogenesis function were assessed in pulmonary artery endothelial cells (PAEC) from control and PPHN lambs. AMPK function was decreased in PPHN PAEC and lung sections. Expression of mitochondrial transcription factor, PGC-1α, ETC complex proteins I-V, and mitochondrial number were decreased in PPHN. In vitro angiogenesis of PAEC and capillary number and vessel volume fraction in the lung were decreased in PPHN. Expression of DLL4 was increased and Jag1 was decreased in PAEC from PPHN lambs. AMPK agonists A769662 and metformin increased the mitochondrial complex proteins and number, in vitro angiogenesis, and Jag1 levels and decreased DLL4 levels in PPHN PAEC. Infusion of metformin in vivo increased the vessel density in PPHN lungs. Decreased AMPK function contributes to impaired angiogenesis in PPHN by altered balance of notch ligands in PPHN.
Author List
Rana U, Callan E, Entringer B, Michalkiewicz T, Joshi A, Parchur AK, Teng RJ, Konduri GGAuthors
Amit Joshi PhD Professor in the Biomedical Engineering department at Medical College of WisconsinGirija Ganesh Konduri MD Chief, 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
Biphenyl Compounds
Ductus Arteriosus
Electron Transport
Endothelial Cells
Enzyme Activation
Female
Hypertension, Pulmonary
Intracellular Signaling Peptides and Proteins
Jagged-1 Protein
Ligands
Lung
Membrane Proteins
Metformin
Mitochondria
Neovascularization, Pathologic
Persistent Fetal Circulation Syndrome
Phosphorylation
Pregnancy
Protein Kinases
Pyrones
Receptors, Notch
Sheep
Thiophenes
Threonine
Transfection