Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

Abstract

Chronic hypoxia induces polycythemia, pulmonary hypertension, right ventricular hypertrophy, and weight loss. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that mediate adaptive responses to hypoxia, including erythropoietin, vascular endothelial growth factor, and glycolytic enzymes. Expression of the HIF-1α subunit increases exponentially as O2 concentration is decreased. Hif1a(-/-) mouse embryos with complete deficiency of HIF-1α due to homozygosity for a null allele at the Hif1a locus die at midgestation, with multiple cardiovascular malformations and mesenchymal cell death. Hif1a(+/-) heterozygotes develop normally and are indistinguishable from Hif1a(+/+) wild-type littermates when maintained under normoxic conditions. In this study, the physiological responses of Hif1a(+/-) and Hif1a(+/+) mice exposed to 10% O2 for one to six weeks were analyzed. Hif1a(+/-) mice demonstrated significantly delayed development of polycythemia, right ventricular hypertrophy, pulmonary hypertension, and pulmonary vascular remodeling and significantly greater weight loss compared with wild-type littermates. These results indicate that partial HIF-1α deficiency has significant effects on multiple systemic responses to chronic hypoxia.