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ResearchIn-Press PreviewPulmonology Open Access | 10.1172/jci.insight.137594

The pentose phosphate pathway mediates hyperoxia-induced lung vascular dysgenesis and alveolar simplification in neonates

Jiannan Gong,1 Zihang Feng,1 Abigail L. Peterson,1 Jennifer F. Carr,1 Xuexin Lu,1 Haifeng Zhao,1 Xiangming Ji,2 You-Yang Zhao,3 Monique E. De Paepe,4 Phyllis A. Dennery,1 and Hongwei Yao1

1Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, United States of America

2Department of Nutrition, Georgia State University, Atlanta, United States of America

3Program for Lung and Vascular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Pathology, Women and Infants Hospital, Providence, United States of America

5Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Rhode Island, United States of America

Find articles by Gong, J. in: JCI | PubMed | Google Scholar

1Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, United States of America

2Department of Nutrition, Georgia State University, Atlanta, United States of America

3Program for Lung and Vascular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Pathology, Women and Infants Hospital, Providence, United States of America

5Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Rhode Island, United States of America

Find articles by Feng, Z. in: JCI | PubMed | Google Scholar |

1Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, United States of America

2Department of Nutrition, Georgia State University, Atlanta, United States of America

3Program for Lung and Vascular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Pathology, Women and Infants Hospital, Providence, United States of America

5Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Rhode Island, United States of America

Find articles by Peterson, A. in: JCI | PubMed | Google Scholar

1Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, United States of America

2Department of Nutrition, Georgia State University, Atlanta, United States of America

3Program for Lung and Vascular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Pathology, Women and Infants Hospital, Providence, United States of America

5Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Rhode Island, United States of America

Find articles by Carr, J. in: JCI | PubMed | Google Scholar

1Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, United States of America

2Department of Nutrition, Georgia State University, Atlanta, United States of America

3Program for Lung and Vascular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Pathology, Women and Infants Hospital, Providence, United States of America

5Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Rhode Island, United States of America

Find articles by Lu, X. in: JCI | PubMed | Google Scholar |

1Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, United States of America

2Department of Nutrition, Georgia State University, Atlanta, United States of America

3Program for Lung and Vascular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Pathology, Women and Infants Hospital, Providence, United States of America

5Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Rhode Island, United States of America

Find articles by Zhao, H. in: JCI | PubMed | Google Scholar

1Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, United States of America

2Department of Nutrition, Georgia State University, Atlanta, United States of America

3Program for Lung and Vascular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Pathology, Women and Infants Hospital, Providence, United States of America

5Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Rhode Island, United States of America

Find articles by Ji, X. in: JCI | PubMed | Google Scholar |

1Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, United States of America

2Department of Nutrition, Georgia State University, Atlanta, United States of America

3Program for Lung and Vascular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Pathology, Women and Infants Hospital, Providence, United States of America

5Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Rhode Island, United States of America

Find articles by Zhao, Y. in: JCI | PubMed | Google Scholar |

1Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, United States of America

2Department of Nutrition, Georgia State University, Atlanta, United States of America

3Program for Lung and Vascular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Pathology, Women and Infants Hospital, Providence, United States of America

5Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Rhode Island, United States of America

Find articles by De Paepe, M. in: JCI | PubMed | Google Scholar

1Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, United States of America

2Department of Nutrition, Georgia State University, Atlanta, United States of America

3Program for Lung and Vascular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Pathology, Women and Infants Hospital, Providence, United States of America

5Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Rhode Island, United States of America

Find articles by Dennery, P. in: JCI | PubMed | Google Scholar

1Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, United States of America

2Department of Nutrition, Georgia State University, Atlanta, United States of America

3Program for Lung and Vascular Biology, Northwestern University Feinberg School of Medicine, Chicago, United States of America

4Department of Pathology, Women and Infants Hospital, Providence, United States of America

5Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Rhode Island, United States of America

Find articles by Yao, H. in: JCI | PubMed | Google Scholar |

Published January 26, 2021 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.137594.
Copyright © 2021, Gong et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 26, 2021 - Version history
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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. Altogether, neonatal hyperoxia augments the PPP, causing abnormal lung EC proliferation, dysmorphic vascular development, and alveolar simplification. These novel observations provide mechanisms and potential metabolic targets to prevent BPD-associated vascular dysgenesis.

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