Bronchopulmonary dysplasia and pulmonary hypertension, or BPD-PH, are serious chronic lung disorders of prematurity, without curative therapies. Hyperoxia, a known causative factor of BPD-PH, activates adenosine monophosphate-activated protein kinase (AMPK) 1 in neonatal murine lungs; however, whether this phenomenon potentiates or mitigates lung injury is unclear. Thus, we hypothesized that (1) endothelial AMPKa1 is necessary to protect neonatal mice against hyperoxia-induced BPD-PH, and (2) AMPKa1 knockdown decreases angiogenesis in hyperoxiaexposed neonatal human pulmonary microvascular endothelial cells (HPMECs). We performed lung morphometric and echocardiographic studies on postnatal day (P) 28 on endothelial AMPKa1- sufficient and -deficient mice exposed to 21% O2 (normoxia) or 70% O2 (hyperoxia) from P1–P14. We also performed tubule formation assays on control- or AMPKa1-siRNA transfected HPMECs, exposed to 21% O2 or 70% O2 for 48 h. Hyperoxia-mediated alveolar and pulmonary vascular simplification, pulmonary vascular remodeling, and PH were significantly amplified in endothelial AMPKa1- deficient mice. AMPKa1 siRNA knocked down AMPKa1 expression in HPMECs, and decreased their ability to form tubules in normoxia and hyperoxia. Furthermore, AMPKa1 knockdown decreased proliferating cell nuclear antigen expression in hyperoxic conditions. Our results indicate that AMPKa1 is required to reduce hyperoxia-induced BPD-PH burden in neonatal mice, and promotes angiogenesis in HPMECs to limit lung injury.
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