Adrenomedullin overexpression protects mice from experimental bronchopulmonary dysplasia and associated pulmonary hypertension

Bronchopulmonary dysplasia (BPD) associated pulmonary hypertension (PH) or BPD-PH is a lung disease of infants with significant morbidity. Adrenomedullin (Adm) is an angiogenic peptide that signals through calcitonin receptor-like receptor (Calcrl) and receptor activity modifying protein 2 (RAMP2). <i>Adm</i> deficiency potentiates hyperoxia-induced experimental BPD-PH in mice; however, whether <i>Adm</i> overexpression can mitigate this lung disease is unclear. Thus, we tested the hypothesis that <i>Adm</i> overexpression attenuates hyperoxia (HO)-induced murine experimental BPD-PH by using a novel transgenic mouse that overexpresses <i>Adm</i> globally (<i>Adm</i>^hi/hi mice). One-day-old <i>Adm</i>^hi/hi mice or their wild-type littermates (<i>Adm</i>^+/+ mice) were exposed to HO ([Formula: see text] 70%) for 14 days and allowed to recover in normoxia (NO, [Formula: see text] 21%) for an additional 14 days. Controls were maintained in NO for 28 days. On postnatal day (P) 14, we harvested the lungs to determine the extent of <i>Adm</i> expression and apoptosis. On P28, we quantified alveolarization, lung vascularization, and PH. HO-exposed <i>Adm</i>^+/+ mice demonstrated increased lung apoptosis, decreased alveolarization and lung vascularization, and indices of PH, indicating that neonatal HO exposure causes BPD-PH. However, <i>Adm</i> overexpression attenuated experimental BPD-PH, as evident by the decreased extent of hyperoxia-induced lung apoptosis and inflammation, alveolar and vascular simplification, pulmonary vascular remodeling, and PH in <i>Adm</i>^hi/hi mice than in <i>Adm</i>^+/+ mice. Collectively, our results demonstrate that <i>Adm</i> overexpression attenuates HO-induced murine experimental BPD-PH, emphasizing the therapeutic potential of Adm for BPD-PH in preterm infants.<b>NEW & NOTEWORTHY</b> The deficiency of the proangiogenic peptide, adrenomedullin (Adm), exacerbates the severe infantile lung disorder, bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH), in mice. However, whether Adm therapy can mitigate this disease is unclear. Our study, conducted with a rigorous methodology, suggests a potential solution. Using a novel mouse that overexpresses Adm to overcome the pharmacological limitations of the peptide, we demonstrate that Adm can mitigate this disorder, highlighting the therapeutic potential of Adm for human BPD-PH.