Collectively, this study identified the KLEIP–Hif-2α axis as a new target for betamethasone, which rescues respiratory failure in KLEIP−/− neonates, and shows two distinct functions for KLEIP in late-stage lung development: firstly, a moderate autocrine function for KLEIP regulating maintenance of embryonic lung endothelial cells and, secondly, a strong angiocrine function of lung capillaries on epithelial pneumocytes via Hif-2α and VEGF (Fig. 5D). Here, KLHL20 is linked to respiratory failure.