Arteriosclerosis in rat aortic allografts: Dynamics of cell growth, apoptosis and expression of extracellular matrix proteins

Abstract

Transplant vasculopathy is a key factor behind the late loss of transplanted organs. Since effective treatment is still lacking, a further understanding of the pathology of this process is important. Here, a rat model of aortic allografts was used and analyzed by immunohistochemistry and biochemical tests. Infrarenal aortic segments were transplanted from F344 to Lewis rats and analysed after 1-12 weeks using isografts as controls. After 1 week, endothelial cells gradually disappeared at the graft lumen as shown by von Willebrand factor staining and cellular activation was detected in the adventitia and intima using cellular retinol-binding protein-1 as a marker. Subsequently, proliferating smooth muscle cells, lymphocytes and macrophages accumulated in the intima as indicated by the appearance of staining for cell- and proliferation-specific antigens (smooth muscle a-actin, CD45_RC, EDI, cyclin D1 and proliferating cell nuclear antigen). After 4-8 weeks, TUNEL- and Fas-positive cells were observed in the media, denoting progressive apoptosis. In parallel, the developing neointima contained increased immunore-activity for fibronectin and osteopontin. At the end of the observation period, an accumulation of macrophages and calcification was observed in the media and endothelial cells reappeared at the graft surface. The findings demonstrate major cellular and structural changes in the transplanted artery, including activation, proliferation and apoptosis of SMCs, and an altered composition of the extracellular matrix. Possibly, the observed changes in SMC phenotype, cell cycle and apoptosis during development of transplant arteriosclerosis are related to the expression of extracellular matrix proteins. (Mol Cell Biochem 249: 75–83, 2003)