Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1

Lisa A. Palmer, Gregg L. Semenza, Mark H. Stoler, Roger A. Johns

Research output: Contribution to journalArticlepeer-review

295 Scopus citations


Type II nitric oxide synthase (NOS) is upregulated in the pulmonary vasculature in a chronic hypoxia model of pulmonary hypertension. In situ hybridization analysis demonstrates that type II NOS RNA is increased in the endothelium as well as in the vascular smooth muscle in the lung. The current studies examine the role of hypoxia-inducible factor (HIF)-1 in regulating type II NOS gene expression in response to hypoxia in pulmonary artery endothelial cells. Northern blot analyses demonstrate a twofold increase in HIF-1α but not in HIF-1β RNA with hypoxia in vivo and in vitro. Electrophoretic mobility shift assays show the induction of specific DNA binding activity when endothelial cells were subjected to hypoxia. This DNA binding complex was identified as HIF-1 using antibodies directed against HIF-1α and HIF-1β. Transient transfection of endothelial cells resulted in a 2.7-fold increase in type II NOS promoter activity in response to hypoxia compared with nonhypoxic controls. Mutation or deletion of the HIF-1 site eliminated the response to hypoxia. These results demonstrate that HIF-1 is essential for the hypoxic regulation of type II NOS gene transcription in pulmonary endothelium.

Original languageEnglish (US)
Pages (from-to)L212-L219
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number2 18-2
StatePublished - 1998
Externally publishedYes


  • Gene regulation
  • Hypoxia-inducible factor-1
  • Nitric oxide
  • Nitric oxide synthase
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology


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