Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 189, Issue 3, Pages 314-324Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.201302-0302OC
Keywords
pulmonary circulation; right ventricular hypertrophy; animal disease models; knock-out mice
Categories
Funding
- National Institutes of Health [HL35440, HL079650, T32 HL76139-7, HL054705, HL102235, HL107577]
- Northwestern University Center for Genetic Medicine Transgenic and Targeted Mutagenesis Laboratory
- Northwestern University Mouse Histology and Phenotyping Laboratory
- Cancer Center Support Grant [NCI CA060553]
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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-1 alpha (HIF-1 alpha) 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-1 alpha 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-1 alpha in smooth muscle on pulmonary vascular and right heart responses to chronic hypoxia. Methods: We used mice with homozygous conditional deletion of HIF-1 alpha 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% O-2) for 30 days before measurement of cardiopulmonary responses. Measurements and Main Results: Tamoxifen-induced smooth muscle-specific deletion of HIF-1 alpha 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-1 alpha 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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