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Though survival rates for preterm infants are improving, the incidence of chronic lung disease of infancy, or bronchopulmonary dysplasia (BPD), remains high. Histologically, BPD is characterized by larger and fewer alveoli. Hypoxia-inducible factors (HIFs) may be protective in the context of hyperoxia-induced lung injury, but the cell-specific effects of HIF expression in neonatal lung injury remain unknown. Thus, we sought to determine whether HIF stabilization in SM22a-expressing cells can limit hyperoxiainduced neonatal lung injury. We generated SM22a-specific HIF-1a-stabilized mice (SM22a-PHD1/2/mice) by cross-breeding SM22a-promotor-driven Cre recombinase mice with prolyl hydroxylase PHD1flox/flox and PHD2flox/flox mice. Neonatal mice were randomized to 21% O2 (normoxia) or 80% O2 (hyperoxia) exposure for 14 days. For the hyperoxia recovery studies, neonatal mice were recovered from normoxia for an additional 10 wk. SM22a-specific HIF-1a stabilization mitigated hyperoxia-induced lung injury and preserved microvessel density compared with control mice for both neonates and adults. In SM22a-PHD1/2/mice, pulmonary artery endothelial cells (PAECs) were more proliferative and pulmonary arteries expressed more collagen IV compared with control mice, even under hyperoxic conditions. Angiopoietin-2 (Ang2) mRNA expression in pulmonary artery smooth muscle cells (PASMC) was greater in SM22a-PHD1/2/compared with control mice in both normoxia and hyperoxia. Pulmonary endothelial cells (PECs) cocultured with PASMC isolated from SM22a-PHD1/2/mice formed more tubes and branches with greater tube length compared with PEC cocultured with PASMC isolated from SM22a-PHD1/2þ/þ mice. Addition of Ang2 recombinant protein further augmented tube formation for both PHD1/2þ/þ and PHD1/2/PASMC. Cell-specific deletion of PHD1 and 2 selectively increases HIF-1a expression in SM22a-expressing cells and protects neonatal lung development despite prolonged hyperoxia exposure. HIF stabilization in SM22a-expressing cells preserved endothelial cell proliferation, microvascular density, increased angiopoietin-2 expression, and lung structure, suggesting a role for cell-specific HIF-1a stabilization to prevent neonatal lung injury. [ABSTRACT FROM AUTHOR]