Heterozygous deficiency of hypoxia-inducible factor–2α protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia

Chronic hypoxia induces pulmonary vascular remodeling, leading to pulmonary hypertension, right ventricular hypertrophy, and heart failure. Heterozygous deficiency of hypoxia-inducible factor–1α (HIF-1α), which mediates the cellular response to hypoxia by increasing expression of genes involved in erythropoiesis and angiogenesis, has been previously shown to delay hypoxia-induced pulmonary hypertension. HIF-2α is a homologue of HIF-1α and is abundantly expressed in the lung, but its role in pulmonary hypertension remains unknown. Therefore, we analyzed the pulmonary response of WT and viable heterozygous HIF-2α–deficient (Hif2α(+/–)) mice after exposure to 10% O(2) for 4 weeks. In contrast to WT mice, Hif2α(+/–) mice were fully protected against pulmonary hypertension and right ventricular hypertrophy, unveiling a critical role of HIF-2α in hypoxia-induced pulmonary vascular remodeling. Pulmonary expression levels of endothelin-1 and plasma catecholamine levels were increased threefold and 12-fold respectively in WT but not in Hif2α(+/–) mice after hypoxia, suggesting that HIF-2α–mediated upregulation of these vasoconstrictors contributes to the development of hypoxic pulmonary vascular remodeling.