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

Olave N, Nicola T, Zhang W, Bulger A, James M, Oparil S, Chen YF, Ambalavanan N. Transforming growth factor-beta regulates endothelin-1 signaling in the newborn mouse lung during hypoxia exposure. Am J Physiol Lung Cell Mol Physiol 302: L857-L865, 2012. First published January 27, 2012; doi: 10.1152/ajplung.00258.2011.-We have previously shown that inhibition of transforming growth factor-beta (TGF-beta) 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-beta 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-beta neutralizing antibody), or vehicle. Lung function and development and TGF-beta and ET-1 synthesis were assessed. Hypoxia inhibited alveolar development, decreased lung compliance, and increased lung resistance. These effects were associated with increased TGF-beta synthesis and signaling and increased ET-1 synthesis. BQ610 (but not BQ788) improved lung function, without altering alveolar development or increased TGF-beta signaling in hypoxia-exposed animals. Inhibition of TGF-beta 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-beta signaling indicates that TGF-beta is upstream of ET-1 during hypoxia-induced signaling in the newborn lung.