Abstract
Bronchopulmonary dysplasia (BPD) is characterized by a severe impairment in lung alveolarization and vascular development. We have previously shown that pulmonary angiogenesis is preserved in hyperoxia-exposed female mice accompanied by increased miR-30a expression, which is a proangiogenic miRNA. Also, miR-30a expression is decreased in human BPD. HIF-1α plays an essential role in postnatal lung development, especially in recovery from hyperoxic injury. Snai1 activation promotes pathological fibrosis through many mechanisms including Endo-MT, which may in turn adversely impact lung vascular development. Our objective was to test the hypothesis that higher miR-30a expression through HIF-1α decreases Snai1 expression in females and attenuates injury in the developing lung. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia (P1-5, 0.95 FiO2) and euthanized on P21. Neonatal human pulmonary microvascular endothelial cells (HPMECs; 18-24-week gestation donors; 3/group either sex) were subjected to hyperoxia (95% O2 and 5% CO2) or normoxia (air and 5% CO2) up to 72 h. Snai1 expression was measured in HPMECs in vitro and in neonatal mouse lungs in vivo. Also, Snai1 expression was measured in HPMECs after miR-30a mimic and miR-30a inhibitor treatment. To further establish the potential regulation of miR-30a by Hif-1α, miR-30a expression after Hif-1α inhibition was measured in HPMECs. In vivo, Snai1 expression was decreased in neonatal female lungs compared to males at P7. Increased Snai1 expression was seen in male HPMECs upon exposure to hyperoxia in vitro. Treatment with the miR-30a mimic decreased Snai1 expression in HPMECs, while miR-30a inhibition significantly increased Snai1 expression in HPMECs. siRNA-mediated loss of Hif-1α expression in HPMECs decreased miR-30a expression. Hif-1α may lead to differential sex-specific miR-30a expression and may contribute to protection from hyperoxic lung injury in female neonatal mice through decreased Snai1 expression.