The role of endothelial HIF-1α in vascular and alveolar development in a neonatal murine model of Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD), a lung disease associated with preterm birth, is characterized by arrested alveolarization and impaired pulmonary vascular growth. Exposure to early-life hyperoxia is a disease-contributing factor, and endothelial determinants of injury versus repair remain incompletely defined. We hypothesized that endothelial-specific loss of Hif-1α during the saccular stage of development would adversely impact lung development and augment injury after hyperoxia exposure. Tamoxifen-inducible endothelial-specific Hif-1α knockout and Hif-1α fl/fl littermates were exposed to room air or 95% O₂ from postnatal day (PND) 1–5, and lungs were analyzed at PND7 and PND21 for morphometry, vascular density, and lung endothelial transcriptomic response. Endothelial Hif-1α deletion had no impact on baseline alveolarization but reduced vascular density under normoxia and significantly worsened hyperoxia-induced alveolar simplification, septal thickening, and vascular rarefaction. Hyperoxia increased endothelial proliferation in both genotypes after 48 hours of recovery in normoxia. Bulk RNA sequencing of the lung endothelial cells revealed a shared hyperoxia injury program (e.g., Inhba, Serpine1 induction; Esm1, Gpihbp1, Car2 suppression). The transcriptomic response in HIF1α ECKO endothelial cells was significantly muted compared to wild-type endothelial cells, lacking induction of Hmox1, Prdx6, and Anxa1. Hif-1α-deficient endothelial cells upregulated Col18a1 and Ackr3 and showed enrichment of TNF–NFκB, TGF-β, and cell-cycle checkpoint pathways, consistent with maladaptive remodeling. Cross-referencing with human single-cell BPD data demonstrated that genes identified in the murine hyperoxia model exhibit conserved but heterogeneous endothelial expression patterns across BPD disease states. These findings identify endothelial Hif-1α as a central determinant of recovery after neonatal hyperoxia exposure.