Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1α

Am J Respir Crit Care Med. 2014 Feb 1;189(3):314-24. doi: 10.1164/rccm.201302-0302OC.


Rationale: Chronic hypoxia induces pulmonary vascular remodeling, pulmonary hypertension, and right ventricular hypertrophy. At present, little is known about mechanisms driving these responses. Hypoxia-inducible factor-1α (HIF-1α) is a master regulator of transcription in hypoxic cells, up-regulating genes involved in energy metabolism, proliferation, and extracellular matrix reorganization. Systemic loss of a single HIF-1α allele has been shown to attenuate hypoxic pulmonary hypertension, but the cells contributing to this response have not been identified.

Objectives: We sought to determine the contribution of HIF-1α in smooth muscle on pulmonary vascular and right heart responses to chronic hypoxia.

Methods: We used mice with homozygous conditional deletion of HIF-1α combined with tamoxifen-inducible smooth muscle-specific Cre recombinase expression. Mice received either tamoxifen or vehicle followed by exposure to either normoxia or chronic hypoxia (10% O2) for 30 days before measurement of cardiopulmonary responses.

Measurements and main results: Tamoxifen-induced smooth muscle-specific deletion of HIF-1α attenuated pulmonary vascular remodeling and pulmonary hypertension in chronic hypoxia. However, right ventricular hypertrophy was unchanged despite attenuated pulmonary pressures.

Conclusions: These results indicate that HIF-1α in smooth muscle contributes to pulmonary vascular remodeling and pulmonary hypertension in chronic hypoxia. However, loss of HIF-1 function in smooth muscle does not affect hypoxic cardiac remodeling, suggesting that the cardiac hypertrophy response is not directly coupled to the increase in pulmonary artery pressure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Airway Remodeling
  • Animals
  • Chronic Disease
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / metabolism*
  • Hypertension, Pulmonary / pathology
  • Hypertrophy, Right Ventricular / etiology
  • Hypertrophy, Right Ventricular / metabolism*
  • Hypertrophy, Right Ventricular / pathology
  • Hypoxia / complications*
  • Hypoxia / metabolism
  • Hypoxia / pathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / deficiency
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Pulmonary Artery / metabolism*
  • Pulmonary Artery / pathology
  • Random Allocation


  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit