VEGF-D Protects the Lung in Neonatal Hyperoxia-induced Lung Injury
- Author(s)
- Wickramasinghe, LC; L'Estrange-Stranieri, E; Cardwell, B; O'Brien, CA; Shad, A; Hsu, AT; van Wijngaarden, P; Anderson, GP; Stacker, SA; Achen, MG; Tsantikos, E; Hibbs, ML;
- Details
- Publication Year 2025-11,Volume 73,Issue #5,Page 790-804
- Journal Title
- American Journal of Respiratory Cell and Molecular Biology
- Publication Type
- Research article
- Abstract
- Bronchopulmonary dysplasia (BPD) is a serious lung disease that affects premature infants born with developmentally immature lungs. Supplemental oxygen, although a lifesaving treatment, provokes inflammation and oxidative stress, causing microvasculature injury, pulmonary edema, and abnormal lung development. Impaired pulmonary vascular development is implicated in BPD; however, the role of the lymphatics is poorly understood. Studies used an established animal model, in which mice were exposed on the day of birth for 14 days to 75% oxygen to induce hallmark features of BPD, including pulmonary edema. Single-cell RNA sequencing data were analyzed to examine VEGF-D (vascular endothelial growth factor-D) expression in the neonatal lung and to define how fibroblasts and lymphatics were altered in response to hyperoxia. VEGF-D biology was interrogated by using mice with a null mutation in Vegfd, and quantitative PCR was used to define mechanisms underlying phenotypes. Hyperoxia elicited expression of VEGF-D, a powerful lymphangiogenic growth factor that is expressed exclusively in lung fibroblasts. In response to hyperoxia, alveolar fibroblasts exhibited significant alterations to their transcriptional profile and changed signaling dynamics within the BPD microenvironment. Probing VEGF-D biology by genetic deletion revealed that VEGF-D deficiency worsened alveolar simplification in response to hyperoxia, exacerbated alveolar fluid accumulation, worsened inflammation, and deranged lymphatic architecture. These data identify an important interplay between alveolar fibroblasts, VEGF-D, and lymphatics in regulating functional lymphangiogenesis and lymphatic vessel patterning in BPD that inform therapeutic and regenerative medicine strategies for this incurable disease.
- Keywords
- Animals; *Hyperoxia/complications/metabolism/pathology; *Vascular Endothelial Growth Factor D/metabolism/genetics; Animals, Newborn; *Lung Injury/metabolism/pathology/etiology; Fibroblasts/metabolism/pathology; Mice; *Lung/metabolism/pathology; *Bronchopulmonary Dysplasia/metabolism/pathology/genetics; Lymphangiogenesis; Disease Models, Animal; Mice, Inbred C57BL; Humans; Vegf-d; alveolar fibroblasts; bronchopulmonary dysplasia; edema; lymphatic vessel remodeling
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1165/rcmb.2024-0544OC
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-07-17 04:27:30
Last Modified: 2026-01-09 02:59:45