Plexiform-like lesions and increased tissue factor expression in a rat model of severe pulmonary arterial hypertension

• Published in: American journal of physiology. Lung cellular and molecular physiology 2007-09, Vol.293 (3), p.L583-L590
• Main Authors: White, R. James, Meoli, David F, Swarthout, Robert F, Kallop, Dara Y, Galaria, Irfan I, Harvey, Jennifer L, Miller, Christine M, Blaxall, Burns C, Hall, Carla M, Pierce, Richard A, Cool, Carlyne D, Taubman, Mark B
• Format: Article
• Language: English
• Subjects: Angiography; Animals; Cell Proliferation - drug effects; Disease Models, Animal; Endothelial Cells - metabolism; Endothelial Cells - pathology; Gene expression; Humans; Hypertension; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - pathology; Hypertrophy, Right Ventricular - chemically induced; Hypertrophy, Right Ventricular - pathology; Lungs; Male; Medical imaging; Monocrotaline - administration & dosage; Monocrotaline - pharmacology; Pneumonectomy; Pulmonary Artery - diagnostic imaging; Pulmonary Artery - drug effects; Pulmonary Artery - metabolism; Pulmonary Artery - pathology; Rats; Rats, Sprague-Dawley; Rodents; Thromboplastin - metabolism; Tissues; Vascular Endothelial Growth Factor Receptor-2 - metabolism; von Willebrand Factor - metabolism
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00321.2006

1 Division of Pulmonary and Critical Care Medicine and 2 Cardiovascular Research Institute, University of Rochester, Rochester, New York; 3 Division of Pulmonary and Critical Care, Washington University School of Medicine, Saint Louis, Missouri; and 4 Department of Pathology, National Jewish Center, Denver, Colorado Submitted 20 August 2006 ; accepted in final form 12 June 2007 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. vascular biology; monocrotaline; neointimal formation; angiography Address for reprint requests and other correspondence: R. J. White, Division of Pulmonary and Critical Care Medicine, Univ. of Rochester, 601 Elmwood Ave., Box 692, Rochester, NY (e-mail: Jim_White{at}urmc.rochester.edu )