Regulation of Hypoxia-induced Pulmonary Hypertension by Vascular Smooth Muscle Hypoxia-Inducible Factor-1alpha

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.

Am J Respir Crit Care Med. 2013 Nov 21; 189(3):314-24

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-1alpha (HIF-1alpha) 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-1alpha 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-1alpha in smooth muscle on pulmonary vascular and right heart responses to chronic hypoxia. Methods: We used mice with homozygous conditional deletion of HIF-1alpha 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-1alpha 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-1alpha 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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