Plasminogen activator inhibitor type 1 inhibits smooth muscle cell proliferation in pulmonary arterial hypertension.
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.
Kouri
Fotini M
FM
Department of Medicine II, University of Giessen Lung Center (UGLC), Justus-Liebig-University, Giessen, Germany.
Queisser
Markus A
MA
Königshoff
Melanie
M
Chrobak
Izabella
I
Preissner
Klaus T
KT
Seeger
Werner
W
Eickelberg
Oliver
O
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
D017395:Plasminogen Activator Inhibitor 1; D053773:Transforming Growth Factor beta1