title: Plasminogen activator inhibitor type 1 inhibits smooth muscle cell proliferation in pulmonary arterial hypertension.
abstract: BACKGROUND
  Pulmonary arterial smooth muscle cells (PASMCs) in the medial layer of the vessel wall are responsible for vessel homeostasis, but also for pathologic vascular remodelling in diseases, such as idiopathic pulmonary arterial hypertension (IPAH). Vascular remodelling in IPAH results in vessel stiffness, occlusion, and increased vascular resistance, but its underlying mechanisms remain to be fully elucidated. In this study, we investigated the expression and function of plasminogen activator inhibitor (PAI)-1, an inhibitor of the plasminogen activator system and target gene of the transforming growth factor (TGF)-beta1 signalling cascade, in PASMC in IPAH.
  
  
  RESULTS
  RNA and protein analysis from lung tissues of donors and patients with IPAH (n=7 each) revealed a significant downregulation of PAI-1 in IPAH lungs. Immunohistochemical analysis localised PAI-1 to the bronchial and alveolar epithelium, as well as to vascular and airway smooth muscle cells. PAI-1 was also downregulated in primary PASMC derived from IPAH lungs as compared with donor-derived PASMC. In order to elucidate PAI-1 function, primary PASMC were stimulated with active recombinant (r)PAI-1, or transfected with PAI-1-specific siRNA. Stimulation with rPAI-1 led to decreased PASMC proliferation and adhesion to vitronectin, and increased PASMC migration. In contrast, PAI-1 knock-down with siRNA increased PASMC proliferation and decreased PASMC migration.
  
  
  CONCLUSIONS
  PAI-1 is significantly downregulated in PASMC in IPAH, on the mRNA and protein level. PAI-1 negatively regulates PASMC proliferation, while it increases PASMC migration. Thus, its loss in IPAH may therefore contribute to pathologic vascular remodelling in IPAH.
authors.affiliation: Department of Medicine II, University of Giessen Lung Center (UGLC), Justus-Liebig-University, Giessen, Germany.
authors.forename: Fotini M
authors.initials: FM
authors.lastname: Kouri
authors.forename: Markus A
authors.initials: MA
authors.lastname: Queisser
authors.forename: Melanie
authors.initials: M
authors.lastname: Königshoff
authors.forename: Izabella
authors.initials: I
authors.lastname: Chrobak
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Preissner
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005786:Gene Expression Regulation; D006262:Health; D006801:Humans; D006973:Hypertension / Q000473:pathology*; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000473:pathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D053773:Transforming Growth Factor beta1