Endothelial to mesenchymal transition during neonatal hyperoxia‐induced pulmonary hypertension

Gong, Jiannan; Feng, Zihang; Peterson, Adam; Carr, Jennifer F.; Vang, Alexander; Braza, Julie; Choudhary, Gaurav; Dennery, Phyllis A.; Yao, Hongwei

doi:10.1002/path.5534

Cited by 26 publications

(13 citation statements)

References 58 publications

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“…We also reported that, in mice, hyperoxic exposure for 3 days as neonates causes pulmonary vascular remodeling, vessel obliteration, and pulmonary hypertension in adulthood (41). Ongoing studies will further determine whether neonatal hyperoxia chronically increases the PPP and EC proliferation, leading to vessel obliteration and subsequent pulmonary hypertension in adulthood.…”

Section: This Indicates That the Ppp And Glycolysis Differentially Comentioning

confidence: 69%

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

Gong¹,

Feng²,

Peterson³

et al. 2021

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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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Section: This Indicates That the Ppp And Glycolysis Differentially Comentioning

confidence: 69%

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

Gong¹,

Feng²,

Peterson³

et al. 2021

JCI Insight

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“…Newborn C57BL/6J mice (<12 h old, male and female) along with their mothers were exposed to room air or hyperoxia (>95% O 2 ) for 72 h in an A-chamber (BioSpherix, Parish, NY) [ 29 , 30 ]. The dams were switched every 24 h between room air and hyperoxia to avoid injury.…”

Section: Methodsmentioning

confidence: 99%

Single-cell transcriptomics reveals lasting changes in the lung cellular landscape into adulthood after neonatal hyperoxic exposure

et al. 2021

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Ventilatory support, such as supplemental oxygen, used to save premature infants impairs the growth of the pulmonary microvasculature and distal alveoli, leading to bronchopulmonary dysplasia (BPD). Although lung cellular composition changes with exposure to hyperoxia in neonatal mice, most human BPD survivors are weaned off oxygen within the first weeks to months of life, yet they may have persistent lung injury and pulmonary dysfunction as adults. We hypothesized that early-life hyperoxia alters the cellular landscape in later life and predicts long-term lung injury. Using single-cell RNA sequencing, we mapped lung cell subpopulations at postnatal day (pnd)7 and pnd60 in mice exposed to hyperoxia (95% O 2 ) for 3 days as neonates. We interrogated over 10,000 cells and identified a total of 45 clusters within 32 cell states. Neonatal hyperoxia caused persistent compositional changes in later life (pnd60) in all five type II cell states with unique signatures and function. Premature infants requiring mechanical ventilation with different durations also showed similar alterations in these unique signatures of type II cell states. Pathologically, neonatal hyperoxic exposure caused alveolar simplification in adult mice. We conclude that neonatal hyperoxia alters the lung cellular landscape in later life, uncovering neonatal programing of adult lung dysfunction.

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“…The sex differences have been replicated in murine models and are strain specific ( 3 , 4 ). Male mice have greater alveolar simplification, impaired pulmonary vascular development, and more long-term adverse sequelae compared with female mice ( 5 , 6 ).…”

Section: Introductionmentioning

confidence: 99%

Effect of sex chromosomes versus hormones in neonatal lung injury

Grimm¹,

Dong²,

Zhang³

et al. 2021

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The main mechanisms underlying sexually dimorphic outcomes in neonatal lung injury are unknown. We tested the hypothesis that hormonal-or sex chromosomemediated mechanisms interact with hyperoxia exposure to impact injury and repair in the neonatal lung. To distinguish sex differences caused by gonadal hormones versus sex chromosome complement (XX versus XY), we used the four core genotypes (FCG) mice and exposed them to hyperoxia (95% FiO2, PND1-4: saccular stage) or room air. This model generates XX and XY mice that each have either testes (with Sry, XXM or XYM) or ovaries (without Sry, XXF or XYF). Lung alveolarization and vascular development were more severely impacted in XYM and XYF compared to XXF and XXM mice. Cell cycle related pathways were enriched in the gonadal or chromosomal females, while muscle related pathways were enriched in the gonadal males, and immune-response related pathways were enriched in chromosomal males. Female gene signatures showed a negative correlation with human patients that developed BPD or needed oxygen therapy at 28 days. These results demonstrate that, chromosomal sex and not gonadal sex impacted the response to neonatal hyperoxia exposure. The female sex chromosomal complement was protective and could mediate sex-specific differences in the neonatal lung injury.

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Endothelial to mesenchymal transition during neonatal hyperoxia‐induced pulmonary hypertension

Cited by 26 publications

References 58 publications

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

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

Single-cell transcriptomics reveals lasting changes in the lung cellular landscape into adulthood after neonatal hyperoxic exposure

Effect of sex chromosomes versus hormones in neonatal lung injury

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