Atherosclerosis shares many properties with chronic inflammatory diseases including the persistent presence of macrophages. It has been suggested that following their emigration from the blood and transformation into foam cells, macrophage release growth factors which stimulate vascular smooth muscle cell (SMC) proliferation and synthesis of extracellular matrix. However, when macrophage are incubated with modified forms of LDL capable of inducing lipid accumulation, their production of growth factor is reduced. In this application, a radically different approach to the study of macrophage and foam cell release of growth factors is proposed. We hypothesize that the enhanced expression of urokinase-type plasminogen activator (uPA) by foam cells leads to the release of extra-cellular matrix bound growth factors, which stimulate both the proliferation of SMC and their synthesis of matrix.
The specific aims of this proposal are as follows: (i) We will characterize and quantify growth factors released by macrophage and foam cells cultured on intact cell-derived matrices in the presence and absence of plasminogen. Growth factors will be identified by bioassay, immunologic and chromatographic methods. (ii) We will determine the effects of cytokines and growth factors on macrophage and foam cell release of matrix bound growth factors. Cellular release of matrix bound growth factors will be correlated with expression of membrane-bound and secreted uPA activities, as well as uPA mRNA levels. (iii) We will determine the relative roles of fluid-phase and membrane-associated activation of plasminogen in macrophage release of matrix bound growth factors. (iv) We will determine the effect of foam cells on SMC proliferation and matrix synthesis utilizing a direct and indirect coculture systems. (v) Finally, we will evaluate uPA expression by foam cells isolated from atherosclerotic rabbit aortas and human atherectomy- samples by immunohistochemistry and in situ hybridization. The long term objectives of these studies is to identify a mechanism by which macrophage and foam cells stimulate atherosclerotic lesion progression in an effort to provide novel approaches toward intervention.
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