Adrenomedullin Is Necessary to Resolve Hyperoxia-Induced Experimental Bronchopulmonary Dysplasia and Pulmonary Hypertension in Mice.

Abstract

Bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) is an infantile lung disease characterized by aberrant angiogenesis and impaired resolution of lung injury. Adrenomedullin (AM) signals through calcitonin receptor-like receptor and receptor activity-modifying protein 2 and modulates lung injury initiation. However, its role in lung injury resolution and the mechanisms by which it regulates angiogenesis remain unclear. Consequently, we hypothesized that AM resolves hyperoxia-induced BPD and PH via endothelial nitric oxide synthase (NOS3). AM-sufficient (ADM+/+) or -deficient (ADM+/-) mice were exposed to normoxia or hyperoxia through postnatal days (PNDs) 1 to 14, and the hyperoxia-exposed mice were allowed to recover in normoxia for an additional 56 days. Lung injury and development and PH were quantified at different time points. Human pulmonary microvascular endothelial cells were also used to examine the effects of AM signaling on the NOS3 pathway and angiogenesis. Lung blood vessels and NOS3 expression decreased and the extent of hyperoxia-induced BPD and PH increased in ADM+/- mice compared with ADM+/+ mice. Hyperoxia-induced apoptosis and PH resolved by PND14 and PND70, respectively, in ADM+/+ mice but not in ADM+/- mice. Knockdown of ADM, calcitonin receptor-like receptor, and receptor activity-modifying protein 2 in vitro decreased NOS3 expression, nitric oxide generation, and angiogenesis. Furthermore, NOS3 knockdown abrogated the angiogenic effects of AM. Collectively, these results indicate that AM resolves hyperoxic lung injury via NOS3.

• Authors: Renuka T Menon, Amrit Kumar Shrestha, Corey L Reynolds, Roberto Barrios, Kathleen M Caron, Binoy Shivanna
• Journal: The American journal of pathology (Am J Pathol) Vol. 190 Issue 3 Pg. 711-722 (03 2020) ISSN: 1525-2191 [Electronic] United States
• PMID: 32093901 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• RAMP2 protein, human
• Receptor Activity-Modifying Protein 2
• Adrenomedullin
• NOS3 protein, human
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse

Topics

• Adrenomedullin (pharmacology)
• Animals
• Bronchopulmonary Dysplasia (drug therapy, etiology, physiopathology)
• Endothelial Cells (pathology)
• Female
• Humans
• Hyperoxia (complications)
• Hypertension, Pulmonary (drug therapy, etiology, physiopathology)
• Lung (physiopathology)
• Lung Injury (drug therapy, physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Nitric Oxide Synthase Type III (genetics, metabolism)
• Receptor Activity-Modifying Protein 2 (genetics, metabolism)
• Signal Transduction