title: Transforming growth factor-β regulates endothelin-1 signaling in the newborn mouse lung during hypoxia exposure.
abstract: We have previously shown that inhibition of transforming growth factor-β (TGF-β) signaling attenuates hypoxia-induced inhibition of alveolar development and abnormal pulmonary vascular remodeling in the newborn mice and that endothelin-A receptor (ETAR) antagonists prevent and reverse the vascular remodeling. The current study tested the hypothesis that inhibition of TGF-β signaling attenuates endothelin-1 (ET-1) expression and thereby reduces effects of hypoxia on the newborn lung. C57BL/6 mice were exposed from birth to 2 wk of age to either air or hypoxia (12% O(2)) while being given either BQ610 (ETAR antagonist), BQ788 (ETBR antagonist), 1D11 (TGF-β neutralizing antibody), or vehicle. Lung function and development and TGF-β and ET-1 synthesis were assessed. Hypoxia inhibited alveolar development, decreased lung compliance, and increased lung resistance. These effects were associated with increased TGF-β synthesis and signaling and increased ET-1 synthesis. BQ610 (but not BQ788) improved lung function, without altering alveolar development or increased TGF-β signaling in hypoxia-exposed animals. Inhibition of TGF-β signaling reduced ET-1 in vivo, which was confirmed in vitro in mouse pulmonary endothelial, fibroblast, and epithelial cells. ETAR blockade improves function but not development of the hypoxic newborn lung. Reduction of ET-1 via inhibition of TGF-β signaling indicates that TGF-β is upstream of ET-1 during hypoxia-induced signaling in the newborn lung.
authors.affiliation: Department of Pediatrics, Univ. of Alabama at Birmingham, Birmingham, AL 35249, USA.
authors.forename: Nelida
authors.initials: N
authors.lastname: Olave
authors.forename: Teodora
authors.initials: T
authors.lastname: Nicola
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Arlene
authors.initials: A
authors.lastname: Bulger
authors.forename: Masheika
authors.initials: M
authors.lastname: James
authors.forename: Suzanne
authors.initials: S
authors.lastname: Oparil
authors.forename: Yiu-Fai
authors.initials: YF
authors.lastname: Chen
authors.forename: Namasivayam
authors.initials: N
authors.lastname: Ambalavanan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology; D015870:Gene Expression; D000860:Hypoxia / Q000378:metabolism*; D008168:Lung / Q000254:growth & development / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D016212:Transforming Growth Factor beta; C087220:BQ 610; C086539:BQ 788