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: Nelida Olave, Teodora Nicola, Wei Zhang, Arlene Bulger, Masheika James, Suzanne Oparil, Yiu-Fai Chen, Namasivayam Ambalavanan
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 302 Issue 9 Pg. L857-65 (May 01 2012) ISSN: 1522-1504 [Electronic] United States
• PMID: 22287612 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelin-1
• Oligopeptides
• Piperidines
• Receptor, Endothelin A
• Receptor, Endothelin B
• Transforming Growth Factor beta
• BQ 610
• BQ 788

Topics

• Animals
• Animals, Newborn
• Cells, Cultured
• Endothelial Cells (metabolism)
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelin-1 (genetics, metabolism, physiology)
• Endothelium, Vascular (cytology)
• Gene Expression
• Hypoxia (metabolism)
• Lung (growth & development, metabolism, pathology, physiopathology)
• Mice
• Mice, Inbred C57BL
• Oligopeptides (pharmacology)
• Piperidines (pharmacology)
• Receptor, Endothelin A (metabolism)
• Receptor, Endothelin B (metabolism)
• Signal Transduction
• Transforming Growth Factor beta (genetics, metabolism, physiology)