Heterozygous deficiency of hypoxia-inducible factor-2alpha protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia

J Clin Invest. 2003 May;111(10):1519-27. doi: 10.1172/JCI15496.


Chronic hypoxia induces pulmonary vascular remodeling, leading to pulmonary hypertension, right ventricular hypertrophy, and heart failure. Heterozygous deficiency of hypoxia-inducible factor-1alpha (HIF-1alpha), which mediates the cellular response to hypoxia by increasing expression of genes involved in erythropoiesis and angiogenesis, has been previously shown to delay hypoxia-induced pulmonary hypertension. HIF-2alpha is a homologue of HIF-1alpha and is abundantly expressed in the lung, but its role in pulmonary hypertension remains unknown. Therefore, we analyzed the pulmonary response of WT and viable heterozygous HIF-2alpha-deficient (Hif2alpha(+/-)) mice after exposure to 10% O(2) for 4 weeks. In contrast to WT mice, Hif2alpha(+/-) mice were fully protected against pulmonary hypertension and right ventricular hypertrophy, unveiling a critical role of HIF-2alpha in hypoxia-induced pulmonary vascular remodeling. Pulmonary expression levels of endothelin-1 and plasma catecholamine levels were increased threefold and 12-fold respectively in WT but not in Hif2alpha(+/-) mice after hypoxia, suggesting that HIF-2alpha-mediated upregulation of these vasoconstrictors contributes to the development of hypoxic pulmonary vascular remodeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atmosphere Exposure Chambers
  • Basic Helix-Loop-Helix Transcription Factors
  • Catecholamines / blood
  • Endothelin-1 / genetics
  • Endothelin-1 / metabolism
  • Fetal Viability / genetics
  • Hematocrit
  • Heterozygote
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / metabolism
  • Hypertension, Pulmonary / pathology
  • Hypertension, Pulmonary / prevention & control*
  • Hypoxia / complications*
  • Lung / blood supply
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Transgenic
  • Phenotype
  • Pulmonary Artery / pathology
  • RNA, Messenger / metabolism
  • Time
  • Trans-Activators / deficiency*
  • Trans-Activators / genetics
  • Up-Regulation
  • Ventricular Dysfunction, Right / etiology
  • Ventricular Dysfunction, Right / prevention & control*


  • Basic Helix-Loop-Helix Transcription Factors
  • Catecholamines
  • Endothelin-1
  • RNA, Messenger
  • Trans-Activators
  • endothelial PAS domain-containing protein 1