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

Chronic hypoxia induces polycyhemia, pulmonary hypertension, right ventricu lar hypertrophy, and weight loss. Hypoxia-inducible factor 1 (HIF-1) activa tes transcription of genes encoding proteins that mediate adaptive response s to hypoxia, including erythropoietin, vascular endothelial growth factor, and glycolytic enzymes. Expression of the HIF-1 alpha subunit increases ex ponentially as O-2 concentration is decreased. Hif1a(-/-) mouse embryos wit h complete deficiency of HIF-1 alpha due to homozygosity for a null allele at the Hif1a locus die at midgestation, with multiple cardiovascular malfor mations and mesenchymal cell death. Hif1a(+/-) heterozygotes develop normal ly and are indistinguishable from Hif1a(+/+) wild-type littermates when mai ntained under normoxic conditions. In this study, the physiological respons es of Hif1a(+/-) and Hif1a(+/+) mice exposed to 10% O-2 for one to six week s were analyzed. Hif1a(+/-) mice demonstrated significantly delayed develop ment of polycythemia, right ventricular hypertrophy, pulmonary hypertension , and pulmonary vascular remodeling and significantly greater weight loss c ompared with wild-type littermates. These results indicate that partial HIF -1 alpha deficiency has significant effects on multiple systemic responses to chronic hypoxia.