title: Haemodynamic unloading reverses occlusive vascular lesions in severe pulmonary hypertension.
abstract: An important pathogenic mechanism in the development of idiopathic pulmonary arterial hypertension is hypothesized to be a cancer-like cellular proliferation independent of haemodynamics. However, because the vascular lesions are inseparably coupled with haemodynamic stress, the fate of the lesions is unknown when haemodynamic stress is eliminated.
  
  
  
  We applied left pulmonary artery banding to a rat model with advanced pulmonary hypertension to investigate the effects of decreased haemodynamic stress on occlusive vascular lesions. Rats were given an injection of the VEGF blocker Sugen5416 and exposed to 3 weeks of hypoxia plus an additional 7 weeks of normoxia (total 10 weeks) (SU/Hx/Nx rats). The banding surgery to reduce haemodynamic stress to the left lung was done at 1 week prior to (preventive) or 5 weeks after (reversal) the SU5416 injection. All SU/Hx/Nx-exposed rats developed severe pulmonary hypertension and right ventricular hypertrophy. Histological analyses showed that the non-banded right lungs developed occlusive lesions including plexiform lesions with marked perivascular cell accumulation. In contrast, banding the left pulmonary artery not only prevented the development of but also reversed the established occlusive lesions as well as perivascular inflammation in the left lungs.
  
  
  
  Our results indicate that haemodynamic stress is prerequisite to the development and progression of occlusive neointimal lesions in this rat model of severe pulmonary hypertension. We conclude that perivascular inflammation and occlusive neointimal arteriopathy are driven by haemodynamic stress.
authors.affiliation: Department of Advanced Cardiovascular Regulation and Therapeutics, Center for Disruptive Cardiovascular Medicine, Kyushu University, Fukuoka 811-1347, Japan.
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Abe
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Shinoda
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan Division of Anesthesiology and Critical Care Medicine, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan.
authors.forename: Yukimitsu
authors.initials: Y
authors.lastname: Kuwabara
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan.
authors.forename: Keimei
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Advanced Cardiovascular Regulation and Therapeutics, Center for Disruptive Cardiovascular Medicine, Kyushu University, Fukuoka 811-1347, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hirooka
authors.affiliation: Department of Pharmacology, University of South Alabama Mobile, 307 N University Blvd #130, Mobile, AL 36608, USA Department of Internal Medicine, University of South Alabama Mobile, 307 N University Blvd #130, Mobile, AL 36608, USA Center for Lung Biology, University of South Alabama Mobile, 307 N University Blvd #130, Mobile, AL 36608, USA.
authors.forename: Ivan F
authors.initials: IF
authors.lastname: McMurtry
authors.affiliation: Department of Pharmacology, University of South Alabama Mobile, 307 N University Blvd #130, Mobile, AL 36608, USA Department of Internal Medicine, University of South Alabama Mobile, 307 N University Blvd #130, Mobile, AL 36608, USA Center for Lung Biology, University of South Alabama Mobile, 307 N University Blvd #130, Mobile, AL 36608, USA moka@southalabama.edu.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Oka
authors.affiliation: Therapeutic Regulation of Cardiovascular Homeostasis, Center for Disruptive Cardiovascular Medicine, Kyushu University, Fukuoka 811-1347, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D020533:Angiogenesis Inhibitors; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D049109:Cell Proliferation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D065627:Familial Primary Pulmonary Hypertension / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006439:Hemodynamics; D000860:Hypoxia / Q000150:complications; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000378:metabolism; D008026:Ligation; D008297:Male; D058426:Neointima; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D011652:Pulmonary Circulation; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D051996:Transcription Factor RelA / Q000378:metabolism; D066253:Vascular Remodeling
chemical_list: D020533:Angiogenesis Inhibitors; D016207:Cytokines; D018836:Inflammation Mediators; C498145:Rela protein, rat; D051996:Transcription Factor RelA
keywords: Haemodynamic stress; Occlusive lesion formation; Pulmonary arterial hypertension