Loss of Hif-2α Rescues the Hif-1α Deletion Phenotype of Neonatal Respiratory Distress In Mice

Hypoxia is a state of decreased oxygen reaching the tissues of the body. During prenatal development, the fetus experiences localized occurrences of hypoxia that are essential for proper organogenesis and survival. The response to decreased oxygen availability is primarily regulated by hypoxia-inducible factors (HIFs), a family of transcription factors that modulate the expression of key genes involved in glycolysis, angiogenesis, and erythropoiesis. HIF-1 alpha and HIF-2 alpha, two key isoforms, are important in embryonic development, and likely are involved in lung morphogenesis. We have recently shown that the inducible loss of Hif-1 alpha in lung epithelium starting at E4.5 leads to death within an hour of parturition, with symptoms similar to neonatal respiratory distress syndrome (RDS). In addition to Hif-1 alpha, Hif-2 alpha is also expressed in the developing lung, although the overlapping roles of Hif-1 alpha and Hif-2 alpha in this context are not fully understood. To further investigate the independent role of Hif-2 alpha in lung epithelium and its ability to alter Hif-1 alpha-mediated lung maturation, we generated two additional lung-specific inducible Hif-alpha knockout models (Hif-2 alpha and Hif-1 alpha + Hif-2 alpha). The intrauterine loss of Hif-2 alpha in the lungs does not lead to decreased viability or observable phenotypic changes in the lung. More interestingly, survivability observed after the loss of both Hif-1 alpha and Hif-2 alpha suggests that the loss of Hif-2 alpha is capable of rescuing the neonatal RDS phenotype seen in Hif-1 alpha-deficient pups. Microarray analyses of lung tissue from these three genotypes identified several factors, such as Scd1, Retln gamma, and Il-1r2, which are differentially regulated by the two HIF-alpha isoforms. Moreover, network analysis suggests that modulation of hormone-mediated, NF-kappa B, C/EBP alpha, and c-MYC signaling are central to HIF-mediated changes in lung development.