title: Plexiform-like lesions and increased tissue factor expression in a rat model of severe pulmonary arterial hypertension.
abstract: Severe pulmonary arterial hypertension (PAH) occurs in idiopathic form and in association with diverse diseases. The pathological hallmarks are distal smooth muscle hypertrophy, obliteration of small pulmonary arteriole lumens, and disorganized cellular proliferation in plexiform lesions. In situ thrombosis is also observed. A detailed understanding of the disease progression has been hampered by the absence of an animal model bearing all the pathological features of human disease. To create a model with these characteristics, we gave young (200-g) rats monocrotaline 1 wk following left pneumonectomy; controls with vehicle treatment or sham operation were also studied. In experimental rats, pulmonary arteries had distal smooth muscle hypertrophy and proliferative perivascular lesions. The lesions had a plexiform appearance, occurred early in disease development, and were composed of cells expressing endothelial antigens. Three-dimensional microangiography revealed severe vascular pruning and disorganized vascular networks. We found that expression of tissue factor (TF), the membrane glycoprotein that initiates coagulation, facilitates angiogenesis, and mediates arterial injury in the systemic circulation, was increased in the pulmonary arterioles and plexiform-like lesions of the rats. TF was also heavily expressed in the vessels and plexiform lesions of humans with pulmonary arterial hypertension. We conclude that plexiform-like lesions can be reproduced in rats, and this model will facilitate experiments to address controversies about the role of these lesions in PAH. Increased TF expression may contribute to the prothrombotic diathesis and vascular cell proliferation typical of human disease.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Univ. of Rochester, 601 Elmwood Ave., Box 692, Rochester, NY, USA. Jim_White@urmc.rochester.edu
authors.forename: R James
authors.initials: RJ
authors.lastname: White
authors.forename: David F
authors.initials: DF
authors.lastname: Meoli
authors.forename: Robert F
authors.initials: RF
authors.lastname: Swarthout
authors.forename: Dara Y
authors.initials: DY
authors.lastname: Kallop
authors.forename: Irfan I
authors.initials: II
authors.lastname: Galaria
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Harvey
authors.forename: Christine M
authors.initials: CM
authors.lastname: Miller
authors.forename: Burns C
authors.initials: BC
authors.lastname: Blaxall
authors.forename: Carla M
authors.initials: CM
authors.lastname: Hall
authors.forename: Richard A
authors.initials: RA
authors.lastname: Pierce
authors.forename: Carlyne D
authors.initials: CD
authors.lastname: Cool
authors.forename: Mark B
authors.initials: MB
authors.lastname: Taubman
mesh_terms: D000792:Angiography; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000473:pathology; D008297:Male; D016686:Monocrotaline / Q000008:administration & dosage / Q000494:pharmacology; D011013:Pneumonectomy; D011651:Pulmonary Artery / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013925:Thromboplastin / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D014841:von Willebrand Factor; D016686:Monocrotaline; D013925:Thromboplastin; D040301:Vascular Endothelial Growth Factor Receptor-2