title: Pulmonary Artery Denervation Attenuates Pulmonary Arterial Remodeling in Dogs With Pulmonary Arterial Hypertension Induced by Dehydrogenized Monocrotaline.
abstract: OBJECTIVE
  This study aimed to investigate sympathetic nerve (SN) ultrastructural changes and hemodynamic and pulmonary artery (PA) pathological improvements by pulmonary arterial denervation (PADN) in animals with pulmonary arterial hypertension (PAH), as well as the underlying mechanisms.
  
  
  BACKGROUND
  SN overactivity plays a role in PAH. Previous studies have reported short-term improvements in pulmonary arterial pressure (PAP) and cardiac function by PADN, but PA remodeling and the associated mechanisms remain unclear.
  
  
  METHODS
  Forty dogs were randomly (ratio of 1:3) assigned to the control (intra-atrial injection of N-dimethylacetamide, 3 mg/kg) and test (intra-atrial injection of dehydrogenized-monocrotaline, 3 mg/kg) groups. After 8 weeks, the animals in the test group with a mean PAP >25 mm Hg (n = 20) were randomized (ratio of 1:1) into the sham and PADN groups. At 14 weeks, the hemodynamics, medial wall thickness and PA muscularization, and messenger ribonucleic acid expression of genes in lung tissues were measured. Another 35 PAH dogs were used to measure the SN conduction velocity, electron microscopic assessment, and nerve distribution.
  
  
  RESULTS
  PADN induced significant SN demyelination and axon loss and slowed SN conduction velocity over time, with resulting profound reductions in the mean PAP (23.5 ± 2.3 mm Hg vs. 33.7 ± 5.8 mm Hg), pulmonary vessel resistance (3.5 ± 2.3 Wood units vs. 7.7 ± 1.7 Wood units), medial wall thickness (22.3 ± 3.3% vs. 30.4 ± 4.1%), and full muscularization (40.3 ± 9.3% vs. 57.1 ± 5.7%) and increased nonmuscularization (29.8 ± 6.1% vs. 12.9 ± 4.9%) compared with the Sham group (all p < 0.001). PADN inhibited the messenger ribonucleic acid expression of genes correlated with inflammation, proliferation, and vasoconstriction.
  
  
  CONCLUSIONS
  PADN induces permanent SN injury and subsequent improvements in hemodynamics and PA remodeling in animals with PAH through mechanisms that may be experimentally and clinically beneficial.
authors.affiliation: Division of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular Research, Nanjing Medical University, Nanjing, China.
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Jiang
authors.affiliation: Division of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Du-Jiang
authors.initials: DJ
authors.lastname: Xie
authors.affiliation: Division of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Jin-Song
authors.initials: JS
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Cardiovascular Research, Nanjing Medical University, Nanjing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Division of Cardiology, Nanjing Heart Center, Nanjing, China.
authors.forename: Zhi-Mei
authors.initials: ZM
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Alexander M K
authors.initials: AMK
authors.lastname: Rothman
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Allan
authors.initials: A
authors.lastname: Lawrie
authors.affiliation: Division of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China; Division of Cardiology, Nanjing Heart Center, Nanjing, China. Electronic address: chmengx@126.com.
authors.forename: Shao-Liang
authors.initials: SL
authors.lastname: Chen
mesh_terms: D000200:Action Potentials; D000818:Animals; D062186:Arterial Pressure; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004285:Dogs; D005786:Gene Expression Regulation; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D016686:Monocrotaline; D009431:Neural Conduction; D011651:Pulmonary Artery / Q000294:innervation* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013562:Sympathectomy; D013564:Sympathetic Nervous System / Q000503:physiopathology / Q000601:surgery* / Q000648:ultrastructure; D013997:Time Factors; D066253:Vascular Remodeling; D014655:Vascular Resistance; D014661:Vasoconstriction
chemical_list: D012333:RNA, Messenger; D016686:Monocrotaline
keywords: electron microscopy; pathological remodeling; pulmonary arterial hypertension; pulmonary artery denervation; sympathetic nerves