title: Potential contribution of phenotypically modulated smooth muscle cells and related inflammation in the development of experimental obstructive pulmonary vasculopathy in rats.
abstract: We tested the hypothesis that phenotypically modulated smooth muscle cells (SMCs) and related inflammation are associated with the progression of experimental occlusive pulmonary vascular disease (PVD). Occlusive PVD was induced by combined exposure to a vascular endothelial growth factor receptor tyrosine kinase inhibitor Sugen 5416 and hypobaric hypoxia for 3 weeks in rats, which were then returned to ambient air. Hemodynamic, morphometric, and immunohistochemical studies, as well as gene expression analyses, were performed at 3, 5, 8, and 13 weeks after the initial treatment (n = 78). Experimental animals developed pulmonary hypertension and right ventricular hypertrophy, and exhibited a progressive increase in indices of PVD, including cellular intimal thickening and intimal fibrosis. Cellular intimal lesions comprised α smooth muscle actin (α SMA)+, SM1+, SM2+/-, vimentin+ immature SMCs that were covered by endothelial monolayers, while fibrous intimal lesions typically included α SMA+, SM1+, SM2+, vimentin+/- mature SMCs. Plexiform lesions comprised α SMA+, vimentin+, SM1-, SM2- myofibroblasts covered by endothelial monolayers. Immature SMC-rich intimal and plexiform lesions were proliferative and were infiltrated by macrophages, while fibrous intimal lesions were characterized by lower proliferative abilities and were infiltrated by few macrophages. Compared with controls, the number of perivascular macrophages was already higher at 3 weeks and progressively increased during the experimental period; gene expression of pulmonary hypertension-related inflammatory molecules, including IL6, MCP1, MMP9, cathepsin-S, and RANTES, was persistently or progressively up-regulated in lungs of experimental animals. We concluded that phenotypically modulated SMCs and related inflammation are potentially associated with the progression of experimental obstructive PVD.
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Otsuki
authors.affiliation: Department of Pediatrics, and Anesthesiology and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sawada
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Yodoya
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan; Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shinohara
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan; Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ohashi
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Erquan
authors.initials: E
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Imanaka-Yoshida
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Shimpo
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komada
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Mitani
mesh_terms: D000818:Animals; D001157:Arterial Occlusive Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005355:Fibrosis; D015870:Gene Expression; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000276:immunology / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010641:Phenotype; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology