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

90 Citations (Scopus)

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

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Hypoxia-Inducible Factor 1
Vascular Smooth Muscle
Pulmonary Hypertension
Smooth Muscle
Tamoxifen
Lung
Right Ventricular Hypertrophy
Pressure
Cardiomegaly
Energy Metabolism
Pulmonary Artery
Extracellular Matrix
Blood Vessels
Hypoxia
Alleles
Genes
Vascular Remodeling

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

Cite this

Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1α. / Ball, Molly K.; Waypa, Gregory B.; Mungai, Paul T.; Nielsen, Jacqueline M.; Czech, Lyubov; Dudley, V. Joseph; Beussink, Lauren; Dettman, Robert W.; Berkelhamer, Sara K.; Steinhorn, Robin H; Shah, Sanjiv J.; Schumacker, Paul T.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 189, No. 3, 01.02.2014, p. 314-324.

Research output: Contribution to journalArticle

Ball, MK, Waypa, GB, Mungai, PT, Nielsen, JM, Czech, L, Dudley, VJ, Beussink, L, Dettman, RW, Berkelhamer, SK, Steinhorn, RH, Shah, SJ & Schumacker, PT 2014, 'Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1α', American Journal of Respiratory and Critical Care Medicine, vol. 189, no. 3, pp. 314-324. https://doi.org/10.1164/rccm.201302-0302OC
Ball, Molly K. ; Waypa, Gregory B. ; Mungai, Paul T. ; Nielsen, Jacqueline M. ; Czech, Lyubov ; Dudley, V. Joseph ; Beussink, Lauren ; Dettman, Robert W. ; Berkelhamer, Sara K. ; Steinhorn, Robin H ; Shah, Sanjiv J. ; Schumacker, Paul T. / Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1α. In: American Journal of Respiratory and Critical Care Medicine. 2014 ; Vol. 189, No. 3. pp. 314-324.
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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.",
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AU - Mungai, Paul T.

AU - Nielsen, Jacqueline M.

AU - Czech, Lyubov

AU - Dudley, V. Joseph

AU - Beussink, Lauren

AU - Dettman, Robert W.

AU - Berkelhamer, Sara K.

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AU - Shah, Sanjiv J.

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AB - 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.

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