Characterization of mouse models for arteriosclerosis in vascular grafts

Allograft accelerated-transplant arteriosclerosis is the main limitation to long-term survival of patients with organ transplantation. A hallmark of lesions is mononuclear cell infiltration into the vessel wall of grafts at the early stage followed by neointimal formation, which largely constitutes of smooth muscle cells. Although the pathogenesis of the disease remains to be studied, it has been observed that the earliest cellular event is leukocyte adhesion to the endothelial surface of the vessel wall within transplanted organs. Subsequently, T cells and monocytes infiltrate into the arterial wall. Several lines of evidence suggest that Intercellular Adhesion Molecule-1 (ICAM-1), a surface glycoprotein of the immunoglobulin superfamily, is involved in a number of inflammatory processes and in arteriosclerosis via mononuclear cell adhesion and migration. However, the molecular mechanisms by which leukocytes are continuously recruited to the vessel wall of grafted organs in vivo is not fully elucidated. Although the tiny body size of mice makes it rather difficult to perform vessel transplantations, the availability of inbred lines and well-defined congenic and recombinant lines in mice facilitates the analysis of genetic factors that contribute to the development of atherosclerotic lesions. The main limitation of the mouse model is its technical complexity, which requires extended training for the operator to become proficient in using the cuff technique. Arterial (common carotid arteries or aorta) and venous (V. cava inf.) vessels were end-to-end allografted into carotid arteries between C57BL/6J and BALB/c mice. Neointimal lesions were observed as early as 2 weeks after surgery and progressed 4 and 6 weeks postoperatively. The lumen of grafted arteries was significantly narrowed due to neointima hyperplasia 4 weeks after transplantation. Using this model, we studied the role of intercellular adhesion molecule-1 (ICAM-1) and of ApoE in the development of transplant arteriosclerosis in ICAM-1- and ApoE-deficient mice, respectively. Neointimal lesions of artery grafts from ICAM-1 -/- donor mice were reduced up to 60% compared to wildtype controls. However, venous grafts from ApoE-knockout donors showed an accelerated formation of atheroma. In addition, we characterized the cell type of the intima-infiltrating cells, and observed that lymphocytes and monocytes initiated the infiltration process, whereas in later stages, migrating smooth muscle cells entail intima thickening and lumen stenosis in grafted vessels. Summarizing out data we can conclude that this model has been proven to be useful for the understanding pathomechanisms of transplant arteriosclerosis. This model is a very helpful tool for basic science as well as for applied research projects and can contribute to the development and establishment of therapeutic strategies against arteriosclerosis in human patients.