The cellular involvement in atherogenesis is now widely acknowledged and is characterized by a specialized, chronic, inflammatory response associated with a fibroproliferative response involving principally smooth muscle cells, monocyte-derived macrophages, T lymphocytes, and, in the very advanced lesions, small blood vessels. However, the cellular components and interactions involved in the process of restenosis postangioplasty, or after bypass surgery, although involving many of the same cell types, are less well understood. This project will continue to test the """"""""Response-to-injury Hypothesis of Atherosclerosis"""""""" as it relates to the pathogenesis of the lesions of atherosclerosis and to the pathogenesis of the process of restenosis. The role of inflammation in restenosis and the capacity of the cells in an advanced lesion of atherosclerosis to respond to the injury induced by an angioplasty- catheter will be examined. A model of restenosis involving angioplasty of advanced lesions in rabbits and, subsequently in later years of the grant, in nonhuman primates will be tested. The roles of inflammation (monocytes and T cells) and smooth muscle cells will be explored. The temporal sequence of cellular events will be determined. Magnetic resonance imaging will be used to follow the progression and possibly regression of the process. Inflammation is a key component in atherogenesis. Therefore, we will pursue the roles of T cells and of specific cell adhesion molecules in monocyte adherence and recruitment into the lesions that form in homozygous transgenic apoprotein E (ApoE)-deficient mice. The formation and disappearance of these molecules on the surface of the aorta and other segments of the arterial tree, with increasing age of the animals and time on the atherogenic diet, will determine which molecules may be involved. The use of inhibitors of adhesion molecules to determine their roles in monocyte and lymphocyte recruitment into the artery wall will be examined in fat fed rabbits and in ApoE-deficient mice. Thus, the importance of the inflammatory response not only in the development of the early lesions but also in their capacity to progress to advanced lesions will be determined using these approaches.
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