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1 Pulmonary & CCM, University of Rochester, Rochester, New York, United States; Cardiovascular Research Institute, University of Rochester, Rochester, New York, United States
2 Pulmonary & CCM, University of Rochester, Rochester, New York, United States
3 Cardiovascular Research Institute, University of Rochester, Rochester, New York, United States
4 Pulmonary Research, Washington University School of Medicine, St. Louis, Missouri, United States
5 Pathology, National Jewish Center, Denver, Colorado, United States
* To whom correspondence should be addressed. E-mail: Jim_White{at}URMC.Rochester.edu.
Severe pulmonary arterial hypertension (PAH) occurs in idiopathic form and in association with diverse diseases. The pathologic 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 pathologic features of human disease. To create a model with these characteristics, we gave young (200 gram) rats monocrotaline one week 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 peri-vascular lesions. The lesions had a plexiform appearance, occurred early in disease development, and were composed of cells expressing endothelial antigens. Three-dimensional micro-angiography 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. Tissue factor 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 tissue factor expression may contribute to the prothrombotic diathesis and vascular cell proliferation typical of human disease.
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