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

• Published in: American journal of respiratory and critical care medicine 2014-02, Vol.189 (3), p.314
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Genes; Hyperplasia; Hypoxia; Metabolism; Pulmonary arteries; Pulmonary hypertension; Smooth muscle; Vascular endothelial growth factor; Veins & arteries
• ISSN: 1073-449X; 1535-4970

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