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

Molly K. Ball, Gregory B. Waypa, Paul T. Mungai, Jacqueline M. Nielsen, Lyubov Czech, V. Joseph Dudley, Lauren Beussink, Robert W. Dettman, Sara K. Berkelhamer, Robin H Steinhorn, Sanjiv J. Shah, Paul T. Schumacker

Research output: Contribution to journalArticle

116 Scopus citations

Abstract

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-1αcombined 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.

Original languageEnglish (US)
Pages (from-to)314-324
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume189
Issue number3
DOIs
StatePublished - Feb 1 2014
Externally publishedYes

Keywords

  • Animal disease models
  • Knock-out mice
  • Pulmonary circulation
  • Right ventricular hypertrophy

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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  • Cite this

    Ball, M. K., Waypa, G. B., Mungai, P. T., Nielsen, J. M., Czech, L., Dudley, V. J., Beussink, L., Dettman, R. W., Berkelhamer, S. K., Steinhorn, R. H., Shah, S. J., & Schumacker, P. T. (2014). Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1α. American Journal of Respiratory and Critical Care Medicine, 189(3), 314-324. https://doi.org/10.1164/rccm.201302-0302OC