Transforming growth factor-β regulates endothelin-1 signaling in the newborn mouse lung during hypoxia exposure.

Academic Article

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.
  • Keywords

  • Animals, Animals, Newborn, Cells, Cultured, Endothelial Cells, Endothelin A Receptor Antagonists, Endothelin B Receptor Antagonists, Endothelin-1, Endothelium, Vascular, Gene Expression, Hypoxia, Lung, Mice, Mice, Inbred C57BL, Oligopeptides, Piperidines, Receptor, Endothelin A, Receptor, Endothelin B, Signal Transduction, Transforming Growth Factor beta
  • Digital Object Identifier (doi)

    Author List

  • Olave N; Nicola T; Zhang W; Bulger A; James M; Oparil S; Chen Y-F; Ambalavanan N
  • Start Page

  • L857
  • End Page

  • L865
  • Volume

  • 302
  • Issue

  • 9