Mechanisms of sex differences in neonatal pulmonary oxygen toxicity

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Bronchopulmonary dysplasia (BPD) is a debilitating lung disease with long-term consequences in premature neonates. Postnatal exposure to high concentrations of oxygen (hyperoxia) contributes to the development of BPD. Premature male neonates are at a greater risk of developing BPD. The reasons underlying sexually dimorphic outcomes in premature neonates are not known. Pulmonary vascular development in neonatal mice exposed to hyperoxia is better preserved in females. Our preliminary analysis of the pulmonary transcriptome demonstrates that angiogenesis is differentially modulated between hyperoxia-exposed neonatal male and female mice. Suggestively, many of these differentially regulated angiogenic transcripts contained a seed sequence for the pro-angiogenic miRNA, miR-30a, within their 3’ UTR. The role of miRNAs in mediating sex biases in BPD is understudied. Relatedly, female lungs had increased miR-30a expression following early exposure to hyperoxia. Compellingly, our preliminary data indicate that protection from neonatal hyperoxic lung injury is lost in female miR30a-/- mice. Hif-1α increases miR-30a expression and plays an important role in post-natal lung development, especially in recovery from hyperoxic injury. HIF-1α binding to its target genes is greater in female lungs after hyperoxia exposure. miR-30a downregulates Delta like ligand 4 (Dll4), which encodes a ligand for the Notch family of receptors. Increased DLL4/Notch activity decreases, while blockade enhances angiogenic sprouting and branching. Decreased miR-30a levels and increased Dll4 and Notch expression are seen in human BPD patient lungs. We hypothesize that higher miR-30a expression through HIF-1α preserves lung vascular development by downregulation of Dll4-Notch signaling in females. The above hypothesis will be tested by the following specific aims: Aim 1: Establish the role of miR-30a in neonatal pulmonary angiogenesis after hyperoxia exposure. Aim 2: Define the sex-specific mechanisms governing transcriptional regulation of miR-30a by HIF-1α during recovery from neonatal hyperoxic lung injury. Aim 3: Determine the impact of endothelial DLL4 suppression by miR-30a in the neonatal lung exposed to hyperoxia. This proposal will address knowledge gaps behind the sexual divergent incidence of bronchopulmonary dysplasia and lay the foundation for future sex-specific treatment strategies.