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May 20, 2026

C107-18 Endothelial HIF-1a Is Essential for Vascular and Alveolar Development in Neonatal Murine Model of Bronchopulmonary Dysplasia

Key Points

This research investigates how endothelial HIF-1α affects vascular and alveolar injury in neonates exposed to hyperoxia, aiming to identify therapeutic targets for bronchopulmonary dysplasia.
Inducible endothelial-specific HIF1α knockout mouse model was created by crossing floxed HIF1α mice with Cre mice.
Mice were exposed to room air or hyperoxia from postnatal days 1-5 and lungs were collected for analysis at PND7 and PND21.
Lung histology and bulk RNA sequencing were conducted to assess alveolar and vascular development.
Endothelial-specific loss of HIF-1α was validated with significant reduction in HIF-1A immunofluorescence in HIF1αECKO mice.
Morphometric analysis indicated impaired alveolarization in HIF1αECKO exposed to hyperoxia, with increased mean linear intercept at PND7.
Bulk RNA sequencing revealed distinct transcriptomic profiles, highlighting dysregulation of inflammatory and vascular development genes.

Abstract

Abstract Background Bronchopulmonary dysplasia (BPD) is a major morbidity in preterm infants, marked by simplified alveoli and impaired vascular development. Hyperoxia drives disease pathogenesis by disrupting angiogenesis, a process essential for normal alveolarization. Lung endothelial cells are highly susceptible to early oxygen-induced injury preceding alveolar arrest. Hypoxia-inducible factor-1α (HIF-1α), a key regulator of angiogenesis, is essential for lung development. This study analyzed the endothelial-specific role of HIF-1α during hyperoxic injury in the saccular phase of lung development and subsequent recovery. Objective To investigate the role of endothelial HIF-1α regulates vascular and alveolar injury in neonates exposed to hyperoxia, aiming to identify potential therapeutic targets for BPD. Methods Inducible endothelial-specific HIF1α knockout (HIF1αECKO) mouse model was generated by crossing HIF1αfl/fl (floxed) mice with Cre (Tg(Cdh5-Cre/ERT2)1Rha) mice carrying the Rosa26-LSL-tdTomato reporter allele (Fig A). Pups received tamoxifen at postnatal days (PND) 1 and 3, followed by exposed to room air (21% FiO2) or hyperoxia (95% FiO2) from PND 1-5, representing the saccular stage. Lungs were collected at PND7 and 21(early and late alveolarization phase) (Fig B). Lung histology was performed to assess alveolar and vascular development. Pulmonary endothelial cells were sorted, and the cellular transcriptome was assessed by bulk RNA sequencing (PND7). Results Endothelial-specific loss of HIF-1α was validated by a marked reduction in endothelial HIF-1A immunofluorescence in HIF1αECKO (Fig C). Morphometric analysis revealed that HIF1αECKO exposed to hyperoxia had significantly increased mean linear intercept at both PND7, indicating impaired alveolarization relative to controls (Fig D). Vascular density was reduced in HIF1αECKO under room air and declined further with hyperoxia in both genotypes, most markedly in HIF1αECKO (Fig E). Bulk RNA sequencing showed distinct transcriptomic profiles between groups; 178 (55%) differentially expressed genes in HIF1αfl/fl, 94 (29%) in HIF1αECKO, and 52 (16%) shared between groups (Fig F). Lung endothelial cells lacking HIF1α showed upregulated genes enriched for inflammatory and immune response, whereas the downregulated genes enriched for vascular development pathways (Fig G-H). Conclusions Loss of HIF-1α amplifies hyperoxia-induced injury, highlighting its role in endothelial resilience. Transcriptomic analysis further revealed dysregulation of inflammatory and vascular developmental genes, thereby identifying potential molecular targets for future therapeutic strategies in BPD. This abstract is funded by: None

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