Pulmonary artery smooth muscle cell endothelin-1 expression modulates the pulmonary vascular response to chronic hypoxia

Am J Physiol Lung Cell Mol Physiol. 2015 Feb 15;308(4):L368-77. doi: 10.1152/ajplung.00253.2014. Epub 2014 Nov 14.


Endothelin-1 (ET-1) increases pulmonary vascular tone through direct effects on pulmonary artery smooth muscle cells (PASMC) via membrane-bound ET-1 receptors. Circulating ET-1 contributes to vascular remodeling by promoting SMC proliferation and migration and inhibiting SMC apoptosis. Although endothelial cells (EC) are the primary source of ET-1, whether ET-1 produced by SMC modulates pulmonary vascular tone is unknown. Using transgenic mice created by crossbreeding SM22α-Cre mice with ET-1(flox/flox) mice to selectively delete ET-1 in SMC, we tested the hypothesis that PASMC ET-1 gene expression modulates the pulmonary vascular response to hypoxia. ET-1 gene deletion and selective activity of SM22α promoter-driven Cre recombinase were confirmed. Functional assays were performed under normoxic (21% O2) or hypoxic (5% O2) conditions using murine PASMC obtained from ET-1(+/+) and ET-1(-/-) mic and in human PASMC (hPASMC) after silencing of ET-1 using siRNA. Under baseline conditions, there was no difference in right ventricular systolic pressure (RVSP) between SM22α-ET-1(-/-) and SM22α-ET-1(+/+) (control) littermates. After exposure to hypoxia (10% O2, 21-24 days), RVSP was and vascular remodeling were less in SM22α-ET-1(-/-) mice compared with control littermates (P < 0.01). Loss of ET-1 decreased PASMC proliferation and migration and increased apoptosis under normoxic and hypoxic conditions. Exposure to selective ET-1 receptor antagonists had no effect on either the hypoxia-induced hPASMC proliferative or migratory response. SMC-specific ET-1 deletion attenuates hypoxia-induced increases in pulmonary vascular tone and structural remodeling. The observation that loss of ET-1 inhibited SMC proliferation, survival, and migration represents evidence that ET-1 derived from SMC plays a previously undescribed role in modulating the response of the pulmonary circulation to hypoxia. Thus PASMC ET-1 may modulate vascular tone independently of ET-1 produced by EC.

Keywords: pulmonary hypertension; smooth muscle cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Cell Survival / genetics
  • Cells, Cultured
  • Chronic Disease
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Endothelin-1 / biosynthesis*
  • Endothelin-1 / genetics
  • Gene Expression Regulation*
  • Gene Silencing
  • Humans
  • Hypoxia / genetics
  • Hypoxia / metabolism*
  • Hypoxia / pathology
  • Hypoxia / physiopathology
  • Mice
  • Mice, Knockout
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Muscle, Smooth, Vascular / physiopathology
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / pathology
  • Pulmonary Artery / metabolism*
  • Pulmonary Artery / pathology
  • Pulmonary Artery / physiopathology
  • Vascular Remodeling / genetics


  • Endothelin-1
  • Microfilament Proteins
  • Muscle Proteins
  • Tagln protein, mouse
  • transgelin