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

Abstract

June 22, 2007; doi:10.1152/ajplung.00321.2006.-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 PULMONARY ARTERIAL HYPERTENSION (PAH) is the marked elevation of precapillary resistance in the pulmonary circulation. It occurs in idiopathic form and in association with such diseases as congenital heart malformation, scleroderma, human immunodeficiency virus (HIV) infection, and cirrhosis (5, 7). There are few effective therapies for PAH, and even with the best available therapy, only 60% of patients live 5 yr, a striking statistic for patients whose mean age is less than 50 (14). While some progress has been made in treating patients, our understanding of the disease pathogenesis remains limited (19).In advanced PAH of many etiologies, endothelial proliferation and medial hypertrophy ultimately obliterate the arterial lumen. Most patients also have disorganized cellular proliferation in glomeruloid structures called plexiform lesions (18,23,33). Plexiform lesions are not seen in systemic arterial disease; however, these unique structures resemble vessels in a rare form of cancer, glioblastoma multiforme (33). Although the role of plexiform lesions in the progression of PAH is controversial, one study of human lung specimens supports the hypothesis that plexiform lesions precede the development of concent...

Cellular microparticles in the pathogenesis of pulmonary hypertension

“…However, PAH pathological specimens often display thrombotic lesions in the absence of clinical or pathological evidence of pulmonary embolism [41], suggesting an in situ clotting phenomenon [42]. Furthermore, PH is associated with a hyper-coagulable phenotype [43] that includes vascular upregulation of tissue factor [44] and an increase in circulating levels of Von Willebrand factor or fibrinopeptide A [45].…”

Egr-1 Expression During Neointimal Development in Flow-Associated Pulmonary Hypertension

“…This finding shows that inflammatory processes, in this case macrophage infiltration, may contribute to neointimal development as seen in end-stage vascular remodeling in human PAH. 29,30 -31 Egr-1 is also located upstream of numerous other genes, such as platelet-derived growth factor 3,5,32 and tissue factor, 9 that participate in PAH. 9 Egr-1 could thus be an important early factor in PAH by regulating different genes involved in neointimal development.…”

“…29,30 -31 Egr-1 is also located upstream of numerous other genes, such as platelet-derived growth factor 3,5,32 and tissue factor, 9 that participate in PAH. 9 Egr-1 could thus be an important early factor in PAH by regulating different genes involved in neointimal development. In systemic vessels, the importance of Egr-1 expression during vascular remodeling has been confirmed given that neointima formation is reduced when Egr-1 expression is blocked.…”

“…We and other investigators have shown that combining monocrotaline with an increased pulmonary blood flow results in pulmonary neointimal lesions in end-stage disease. [7][8][9][10] Little is known about the development of these lesions during disease progression.In a rat model of flow-associated PAH, we recently identified the early growth response protein 1 (Egr-1) transcription factor, by microarray analysis, to be upregulated in end-stage PAH only when increased pulmonary blood flow was added to monocrotaline administration. 8 Egr-1 is expressed in a variety of cardiovascular…”

“…We and other investigators have shown that combining monocrotaline with an increased pulmonary blood flow results in pulmonary neointimal lesions in end-stage disease. [7][8][9][10] Little is known about the development of these lesions during disease progression.…”