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Bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) is a significant lung morbidity of infants, and disrupted lung angiogenesis is a hallmark of this disease. We observed that extracellular signal-regulated kinases (ERK) 1/2 support angiogenesis in vitro, and hyperoxia activates ERK1/2 in fetal human pulmonary microvascular endothelial cells (HPMECs) and in neonatal murine lungs; however, their role in experimental BPD and PH is unknown. Therefore, we hypothesized that  Tie2  Cre-mediated deficiency of  ERK2  in the endothelial cells of neonatal murine lungs would potentiate hyperoxia-induced BPD and PH. We initially determined the role of  ERK2  in in vitro angiogenesis using fetal HPMECs. To disrupt endothelial  ERK2  signaling in the lungs, we decreased  ERK2  expression by breeding  ERK2  flox/flox  mice with  Tie -Cre mice. One-day-old endothelial  ERK2 -sufficient ( eERK2  +/+ ) or –deficient ( eERK2  +/− ) mice were exposed to normoxia or hyperoxia (FiO 2  70%) for 14 d. We then performed lung morphometry, gene and protein expression studies, and echocardiography to determine the extent of inflammation, oxidative stress, and development of lungs and PH. The knockdown of  ERK2  in HPMECs decreased in vitro angiogenesis. Hyperoxia increased lung inflammation and oxidative stress, decreased lung angiogenesis and alveolarization, and induced PH in neonatal mice; however, these effects were augmented in the presence of  Tie2 -Cre mediated endothelial  ERK2  deficiency. Therefore, we conclude that endothelial  ERK2  signaling is necessary to mitigate hyperoxia-induced experimental BPD and PH in neonatal mice. Our results indicate that endothelial ERK2 is a potential therapeutic target for the management of BPD and PH in infants.

international journal of molecular sciences

Tie-2 Cre-Mediated Deficiency of Extracellular Signal-Regulated Kinase 2 Potentiates Experimental Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension in Neonatal Mice