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(American Journal of Pathology. 2009;174:782-796.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080345

Neprilysin Null Mice Develop Exaggerated Pulmonary Vascular Remodeling in Response to Chronic Hypoxia

Edward C. Dempsey*{dagger}{ddagger}, Marilee J. Wick*{ddagger}, Vijaya Karoor*, Erica J. Barr*{ddagger}, Dustin W. Tallman*, Carol A. Wehling{ddagger}, Sandra J. Walchak*, Sven Laudi§, Mysan Le{ddagger}, Masahiko Oka*, Susan Majka*, Carlyne D. Cool¶||, Karen A. Fagan*, Dwight J. Klemm*{ddagger}, Louis B. Hersh**, Norma P. Gerard{dagger}{dagger}, Craig Gerard{dagger}{dagger} and York E. Miller{dagger}{ddagger}

From the Cardiovascular Pulmonary Research Laboratory,* the University of Colorado Cancer Center,{dagger} and the Departments of Anesthesiology,§ and Pathology, University of Colorado at Denver and Health Sciences Center, Denver, Colorado; the Pulmonary and Critical Care Section,{ddagger} Denver VA Medical Center, Denver, Colorado; the Department of Medicine,|| National Jewish Medical and Research Center, Denver, Colorado; the Department of Molecular and Cellular Biochemistry,** University of Kentucky, College of Medicine, Lexington, Kentucky; and the Pulmonary Division,{dagger}{dagger} Department of Pediatrics, Children’s Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts

Neprilysin is a transmembrane metalloendopeptidase that degrades neuropeptides that are important for both growth and contraction. In addition to promoting carcinogenesis, decreased levels of neprilysin increases inflammation and neuroendocrine cell hyperplasia, which may predispose to vascular remodeling. Early pharmacological studies showed a decrease in chronic hypoxic pulmonary hypertension with neprilysin inhibition. We used a genetic approach to test the alternate hypothesis that neprilysin depletion increases chronic hypoxic pulmonary hypertension. Loss of neprilysin had no effect on baseline airway or alveolar wall architecture, vessel density, cardiac function, hematocrit, or other relevant peptidases. Only lung neuroendocrine cell hyperplasia and a subtle neuropeptide imbalance were found. After chronic hypoxia, neprilysin-null mice exhibited exaggerated pulmonary hypertension and striking increases in muscularization of distal vessels. Subtle thickening of proximal media/adventitia not typically seen in mice was also detected. In contrast, adaptive right ventricular hypertrophy was less than anticipated. Hypoxic wild-type pulmonary vessels displayed close temporal and spatial relationships between decreased neprilysin and increased cell growth. Smooth muscle cells from neprilysin-null pulmonary arteries had increased proliferation compared with controls, which was decreased by neprilysin replacement. These data suggest that neprilysin may be protective against chronic hypoxic pulmonary hypertension in the lung, at least in part by attenuating the growth of smooth muscle cells. Lung-targeted strategies to increase neprilysin levels could have therapeutic benefits in the treatment of this disorder.


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