Arteriosclerosis in rat aortic allografts: early changes in endothelial integrity and smooth muscle phenotype.

摘要

BACKGROUND: Transplant arteriosclerosis remains a limiting factor for the long-term survival of transplanted organs and effective treatment is lacking. A rat model of aortic allografts was used to analyze this process by electron microscopy and further characterize the phenotypic properties of the cells involved. METHODS: A segment of abdominal aorta was transplanted orthotopically from Fischer to Lewis rats. The animals were killed 1-12 weeks after the operation (four to six rats/group), and the grafts were removed and processed for microscopy. RESULTS: The first changes (1 week) included detachment of endothelial cells, adhesion of degranulating platelets to the subendothelial matrix, and modification of smooth muscle cells in the media. The latter process was distinguished by loss of myofilaments and formation of a prominent endoplasmic reticulum and Golgi complex (shift from contractile to synthetic phenotype). Subsequently, modified smooth muscle cells invaded the intima. In parallel, lymphocytes and monocytes/macrophages infiltrated the intima and adventitia. The neointima grew in size by cell proliferation and production of extracellular matrix (4-8 weeks). Smooth muscle cells and monocytes/macrophages in the neointima and media were also noted to accumulate cytoplasmic lipid droplets and eventually turn into foam cells and die. Within the lipid-rich cell remnants, calcification occurred. Finally (12 weeks), the growth in mass of the intimal lesions ceased and in some places reformation of an endothelial lining was detected. Few viable smooth muscle cells remained in the media and the inflammatory infiltrate in the adventitia was reduced. CONCLUSIONS: These observations highlight the importance of early changes in endothelial integrity and smooth muscle phenotype in the development of allograft vascular disease and form the basis for a partly modified model of the cellular mechanisms in this process.