Related Experiment Video
Updated: May 12, 2025
Isolation of Pulmonary Artery Smooth Muscle Cells from Neonatal Mice
Published on: October 19, 2013
VEGF-D Protects the Lung in Neonatal Hyperoxia-induced Lung Injury
Lakshanie C Wickramasinghe1, Elan L'Estrange-Stranieri1, Bailey Cardwell1
1Department of Immunology, School of Translational Medicine, Monash University, Melbourne, Victoria, Australia.
Insights
Supplemental oxygen worsens bronchopulmonary dysplasia (BPD) by damaging lungs. Fibroblast-derived VEGF-D is crucial for lymphatic development in BPD, and its absence exacerbates lung injury and inflammation.
Area of Science:
- Neonatal lung development and disease
- Vascular biology
- Fibroblast and lymphatic interactions
Background:
- Bronchopulmonary dysplasia (BPD) affects premature infants, with supplemental oxygen causing lung injury.
- Pulmonary vascular development is impaired in BPD, but lymphatic roles remain unclear.
Purpose of the Study:
- Investigate the role of vascular endothelial growth factor-D (VEGF-D) in neonatal lung response to hyperoxia.
- Define how fibroblasts and lymphatics are altered in BPD.
- Explore therapeutic targets for BPD.
Main Methods:
- Utilized a mouse model of hyperoxia-induced BPD.
- Analyzed single-cell RNA sequencing data for VEGF-D expression and fibroblast/lymphatic changes.
- Employed genetic deletion of Vegfd and qPCR to study mechanisms.
Main Results:
- Hyperoxia increased VEGF-D expression in lung fibroblasts.
- Alveolar fibroblasts showed altered transcriptional profiles under hyperoxia.
- Vegfd deficiency worsened BPD features, including alveolar simplification, edema, and inflammation, and disrupted lymphatic architecture.
Conclusions:
- Alveolar fibroblasts and VEGF-D are critical for lymphangiogenesis and lymphatic patterning in BPD.
- Targeting the fibroblast-VEGF-D-lymphatic axis may offer therapeutic strategies for BPD.
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.
