Endothelial Adenosine Monophosphate-Activated Protein Kinase-Alpha1 Deficiency Potentiates Hyperoxia-Induced Experimental Bronchopulmonary Dysplasia and Pulmonary Hypertension

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) alpha 1 in neonatal murine lungs; however, whether this phenomenon potentiates or mitigates lung injury is unclear. Thus, we hypothesized that (1) endothelial AMPK alpha 1 is necessary to protect neonatal mice against hyperoxia-induced BPD-PH, and (2) AMPK alpha 1 knockdown decreases angiogenesis in hyperoxia-exposed neonatal human pulmonary microvascular endothelial cells (HPMECs). We performed lung morphometric and echocardiographic studies on postnatal day (P) 28 on endothelial AMPK alpha 1-sufficient and -deficient mice exposed to 21% O-2 (normoxia) or 70% O-2 (hyperoxia) from P1-P14. We also performed tubule formation assays on control- or AMPK alpha 1-siRNA transfected HPMECs, exposed to 21% O-2 or 70% O-2 for 48 h. Hyperoxia-mediated alveolar and pulmonary vascular simplification, pulmonary vascular remodeling, and PH were significantly amplified in endothelial AMPK alpha 1-deficient mice. AMPK alpha 1 siRNA knocked down AMPK alpha 1 expression in HPMECs, and decreased their ability to form tubules in normoxia and hyperoxia. Furthermore, AMPK alpha 1 knockdown decreased proliferating cell nuclear antigen expression in hyperoxic conditions. Our results indicate that AMPK alpha 1 is required to reduce hyperoxia-induced BPD-PH burden in neonatal mice, and promotes angiogenesis in HPMECs to limit lung injury.