Transplantation-associated arteriosclerosis (TxAA) is an intimal lesion composed predominantly of smooth muscle-like cells and associated matrix proteins, admixed with mononuclear inflammatory cells. TxAA causes progressive vascular occlusion allograft ischemia; it represents the major long-term limitation to solid organ transplantation. Although TxAA is largely ascribed to an immune-mediated allogeneic response, it can occur in isografts, does not correlate strictly with episodes or severity of acute allograft rejection, and is observed even in the setting of immunosuppression adequate to block acute parenchymal rejection. Thus, we hypothesize that endothelial injury or dysfunction caused by a variety of vascular insults induces a chronic healing response characterized by the recruitment and activation of smooth muscle-like cells (SMLC). Proliferation of these cells with ongoing matrix synthesis forms the basis of the TxAA lesions. Whether these SMLC derive from donor medial smooth muscle cells (SMC) or from host cells has important implications for targeting therapeutic intervention in TxAA, as well as in more conventional atherosclerosis. Using aortic and heart murine transplantation models, we previously demonstrated that intimal SMLC overwhelmingly derive from host cells including host bone marrow precursors. Building on these earlier observations, the Specific Aims of this proposal are to: i) Test the hypothesis that intimal SMLC in TxAA derive from both host bone marrow (BM) as well as host non-BM precursor cells. Utilizing adoptive transfer of selected cell populations, these experiments will also determine whether the relevant BM cells have an hematopoietic or non-hematopoietic origin. ii) Test the hypothesis that the SMLC in TxAA lesions are recruited by pathways different from those used by inflammatory cells that mediate acute allograft rejection, including distinct chemokine and/or chemokine receptor usage, as well as adhesion molecule pairs. We will also use aortic allografts with non-permeant adventitial surfaces to test whether SMLC precursors access grafts by lumenal or ablumenal approaches. iii) Test the hypothesis that the intimal SMLC constitute a cell population with proliferative features and cytokine responses functionally different than medial SMC or inflammatory cells. This work involves the characterization of cultured SMC or SMLC from different sources including TxAA lesions and BM precursors.
| Shimizu, Koichi; Minami, Manabu; Shubiki, Rica et al. (2009) CC chemokine receptor-1 activates intimal smooth muscle-like cells in graft arterial disease. Circulation 120:1800-13 |
| Mitchell, Richard N (2009) Graft vascular disease: immune response meets the vessel wall. Annu Rev Pathol 4:19-47 |
| Okamoto, Yoshihisa; Christen, Thomas; Shimizu, Koichi et al. (2009) Adiponectin inhibits allograft rejection in murine cardiac transplantation. Transplantation 88:879-83 |
| Noma, Kensuke; Rikitake, Yoshiyuki; Oyama, Naotsugu et al. (2008) ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury. J Clin Invest 118:1632-44 |
| Shimizu, Koichi; Libby, Peter; Shubiki, Rica et al. (2008) Leukocyte integrin Mac-1 promotes acute cardiac allograft rejection. Circulation 117:1997-2008 |
| Isoda, Kikuo; Folco, Eduardo J; Shimizu, Koichi et al. (2007) AGE-BSA decreases ABCG1 expression and reduces macrophage cholesterol efflux to HDL. Atherosclerosis 192:298-304 |
| Mitchell, Richard N; Libby, Peter (2007) Vascular remodeling in transplant vasculopathy. Circ Res 100:967-78 |
| Sugiyama, Seigo; Kugiyama, Kiyotaka; Nakamura, Shinichi et al. (2006) Characterization of smooth muscle-like cells in circulating human peripheral blood. Atherosclerosis 187:351-62 |
| Shimizu, Koichi; Mitchell, Richard N; Libby, Peter (2006) Inflammation and cellular immune responses in abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 26:987-94 |
| Shimizu, Koichi; Libby, Peter; Mitchell, Richard N (2005) Local cytokine environments drive aneurysm formation in allografted aortas. Trends Cardiovasc Med 15:142-8 |
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