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Updated: Nov 20, 2025
Isolation of Pulmonary Artery Smooth Muscle Cells from Neonatal Mice
Published on: October 19, 2013
The pentose phosphate pathway mediates hyperoxia-induced lung vascular dysgenesis and alveolar simplification in
Jiannan Gong1,2, Zihang Feng1, Abigail L Peterson1
1Department of Molecular Biology, Cell Biology & Biochemistry, Division of Biology and Medicine, Brown University, Providence, Rhode Island, USA.
Insights
Neonatal hyperoxia disrupts lung vascular development by increasing the pentose phosphate pathway (PPP), leading to abnormal endothelial cell proliferation and alveolar simplification in premature infants.
Area of Science:
- Pulmonary Medicine
- Developmental Biology
- Metabolic Pathways
Background:
- Bronchopulmonary dysplasia (BPD) in premature infants involves paradoxical dysmorphic pulmonary vascular growth and abnormal endothelial cell (EC) proliferation despite vascular pruning.
- The pentose phosphate pathway (PPP), crucial for NADPH and nucleotide synthesis, is implicated in cellular redox balance and proliferation.
- Hyperoxia is a known mediator of BPD, but its effects on glycolysis and PPP in lung ECs remain unclear.
Purpose of the Study:
- To investigate whether hyperoxia alters glycolysis and the PPP in lung ECs.
- To determine if hyperoxia-induced changes in these pathways contribute to abnormal EC proliferation and dysmorphic angiogenesis in neonatal mice.
Main Methods:
- Exposure of lung ECs and newborn mice to hyperoxia, followed by recovery in air.
- Assessment of glycolysis and PPP activity.
- Genetic manipulation (overexpression of phosphogluconate dehydrogenase) and pharmacological inhibition of the PPP.
- Evaluation of EC proliferation, vascular morphology, and alveolar structure.
Main Results:
- Hyperoxia increased both glycolysis and PPP activity in lung ECs.
- Increased PPP activity, not glycolysis, directly caused hyperoxia-induced abnormal EC proliferation.
- Inhibition of the PPP reduced hyperoxia-induced glucose-derived deoxynucleotide synthesis and attenuated abnormal lung development in vivo.
- Overexpression of a key PPP enzyme augmented hyperoxia-induced lung EC proliferation and dysmorphic angiogenesis.
Conclusions:
- Neonatal hyperoxia significantly augments the pentose phosphate pathway in the lungs.
- This PPP augmentation drives abnormal lung EC proliferation, dysmorphic vascular development, and alveolar simplification, contributing to BPD pathogenesis.
- Targeting the PPP presents a potential therapeutic strategy to prevent BPD-associated vascular dysgenesis.
Abstract:
Dysmorphic pulmonary vascular growth and abnormal endothelial cell (EC) proliferation are paradoxically observed in premature infants with bronchopulmonary dysplasia (BPD), despite vascular pruning. The pentose phosphate pathway (PPP), a metabolic pathway parallel to glycolysis, generates NADPH as a reducing equivalent and ribose 5-phosphate for nucleotide synthesis. It is unknown whether hyperoxia, a known mediator of BPD in rodent models, alters glycolysis and the PPP in lung ECs. We hypothesized that hyperoxia increases glycolysis and the PPP, resulting in abnormal EC proliferation and dysmorphic angiogenesis in neonatal mice. To test this hypothesis, lung ECs and newborn mice were exposed to hyperoxia and allowed to recover in air. Hyperoxia increased glycolysis and the PPP. Increased PPP, but not glycolysis, caused hyperoxia-induced abnormal EC proliferation. Blocking the PPP reduced hyperoxia-induced glucose-derived deoxynucleotide synthesis in cultured ECs. In neonatal mice, hyperoxia-induced abnormal EC proliferation, dysmorphic angiogenesis, and alveolar simplification were augmented by nanoparticle-mediated endothelial overexpression of phosphogluconate dehydrogenase, the second enzyme in the PPP. These effects were attenuated by inhibitors of the PPP. Neonatal hyperoxia augments the PPP, causing abnormal lung EC proliferation, dysmorphic vascular development, and alveolar simplification. These observations provide mechanisms and potential metabolic targets to prevent BPD-associated vascular dysgenesis.
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