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.
Highlights
Babies born prematurely have underdeveloped lungs that do not facilitate proper gas exchange; they need respiratory support, including supplemental oxygen and/or mechanical ventilation, as lifesaving measures
endothelial cell (EC) rely on glycolysis for generating bioenergetics [10, 11], it is not known whether hyperoxic exposure alters glycolysis in lung ECs
Proton efflux rate from glycolysis was increased in lung ECs exposed to hyperoxia (Figure 1B)
Summary
Babies born prematurely have underdeveloped lungs that do not facilitate proper gas exchange; they need respiratory support, including supplemental oxygen and/or mechanical ventilation, as lifesaving measures These therapies can cause bronchopulmonary dysplasia (BPD), a chronic lung disease, which affects 10,000–15,000 premature infants annually in the USA. The expansion of the pulmonary microvasculature is associated with increased proliferation of lung endothelial cells (ECs) [8] These capillaries locate in the lung interstitium and do not align beneath the airway epithelium, retaining the primitive vascular pattern of a double-layered capillary network, all of which leads to ineffective gas exchange [8, 9]. The mechanisms underlying these abnormally shaped and malpositioned vessels in BPD are not known
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