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-1αfl/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 h 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 HIF1αECKO endothelial cells was significantly muted compared with 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-NF-κB, 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.NEW & NOTEWORTHY This study identifies endothelial hypoxia-inducible factor-1α (HIF-1α) as a critical determinant of neonatal lung response to hyperoxia. Using an inducible endothelial-specific Hif-1α knockout model, we demonstrate that loss of endothelial Hif-1α exacerbates hyperoxia-induced impairments in pulmonary vascular development and alveolarization, key pathological features of bronchopulmonary dysplasia.