title: Neprilysin null mice develop exaggerated pulmonary vascular remodeling in response to chronic hypoxia.
abstract: 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.
authors.affiliation: Cardiovascular Pulmonary Research Laboratory; B-133, University of Colorado Denver, 12700 E. 19 Ave, Aurora, CO 80046, USA. edward.dempsey@ucdenver.edu
authors.forename: Edward C
authors.initials: EC
authors.lastname: Dempsey
authors.forename: Marilee J
authors.initials: MJ
authors.lastname: Wick
authors.forename: Vijaya
authors.initials: V
authors.lastname: Karoor
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Barr
authors.forename: Dustin W
authors.initials: DW
authors.lastname: Tallman
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wehling
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Walchak
authors.forename: Sven
authors.initials: S
authors.lastname: Laudi
authors.forename: Mysan
authors.initials: M
authors.lastname: Le
authors.forename: Masahiko
authors.initials: M
authors.lastname: Oka
authors.forename: Susan
authors.initials: S
authors.lastname: Majka
authors.forename: Carlyne D
authors.initials: CD
authors.lastname: Cool
authors.forename: Karen A
authors.initials: KA
authors.lastname: Fagan
authors.forename: Dwight J
authors.initials: DJ
authors.lastname: Klemm
authors.forename: Louis B
authors.initials: LB
authors.lastname: Hersh
authors.forename: Norma P
authors.initials: NP
authors.lastname: Gerard
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
authors.forename: York E
authors.initials: YE
authors.lastname: Miller
mesh_terms: D000818:Animals; D002455:Cell Division; D002908:Chronic Disease; D017931:DNA Primers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000473:pathology*; D000860:Hypoxia / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D015260:Neprilysin / Q000172:deficiency* / Q000235:genetics; D011651:Pulmonary Artery / Q000473:pathology*; D011652:Pulmonary Circulation / Q000502:physiology*
chemical_list: D017931:DNA Primers; D015260:Neprilysin; C530673:neprilysin 2, mouse