Publication Date
8-8-2023
Journal
Biology of Sex Differences
DOI
10.1186/s13293-023-00535-6
PMID
37553579
PMCID
PMC10408139
PubMedCentral® Posted Date
8-8-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Female, Male, Mice, Animals, Newborn, Bronchopulmonary Dysplasia, Hyperoxia, Lung, Lung Injury, MicroRNAs, Sex Factors
Abstract
BACKGROUND: Bronchopulmonary dysplasia (BPD) is characterized by an arrest in lung development and is a leading cause of morbidity in premature neonates. It has been well documented that BPD disproportionally affects males compared to females, but the molecular mechanisms behind this sex-dependent bias remain unclear. Female mice show greater preservation of alveolarization and angiogenesis when exposed to hyperoxia, accompanied by increased miR-30a expression. In this investigation, we tested the hypothesis that loss of miR-30a would result in male and female mice experiencing similar impairments in alveolarization and angiogenesis under hyperoxic conditions.
METHODS: Wild-type and miR-30a−/− neonatal mice were exposed to hyperoxia [95% FiO2, postnatal day [PND1-5] or room air before being euthanized on PND21. Alveolarization, pulmonary microvascular development, differences in lung transcriptome, and miR-30a expression were assessed in lungs from WT and miR-30a−/− mice of either sex. Blood transcriptomic signatures from preterm newborns (with and without BPD) were correlated with WT and miR-30a−/− male and female lung transcriptome data.
RESULTS: Significantly, the sex-specific differences observed in WT mice were abrogated in the miR-30a−/− mice upon exposure to hyperoxia. The loss of miR-30a expression eliminated the protective effect in females, suggesting that miR-30a plays an essential role in regulating alveolarization and angiogenesis. Transcriptome analysis by whole lung RNA-Seq revealed a significant response in the miR-30a−/− female hyperoxia-exposed lung, with enrichment of pathways related to cell cycle and neuroactive ligand–receptor interaction. Gene expression signature in the miR-30a−/− female lung associated with human BPD blood transcriptomes. Finally, we showed the spatial localization of miR-30a transcripts in the bronchiolar epithelium.
CONCLUSIONS: miR-30a could be one of the biological factors mediating the resilience of the female preterm lung to neonatal hyperoxic lung injury. A better understanding of the effects of miR-30a on pulmonary angiogenesis and alveolarization may lead to novel therapeutics for treating BPD.
Included in
Biological Phenomena, Cell Phenomena, and Immunity Commons, Life Sciences Commons, Medical Cell Biology Commons, Medical Microbiology Commons, Medical Molecular Biology Commons, Medical Specialties Commons
Comments
Associated Data