The emigration of monocytes from the circulation to a subendothelial position, and their subsequent transformation into cholesteryl ester rich foam cells is one of the earliest recognizable processes in lesion formation. In proposed experiments, aspects of macrophage function thought to play a role in vascular biology will be assessed. In particular, we will investigate macrophage-derived foam cells' release and/or activation of extracellular proteases. Secretion of soluble plasminogen activator and expression of membrane associated activator will be determined. The activity of other neutral proteases will also be assessed including that of collagenase. In addition to the important role of macrophage in connective tissue degradation and fibrinolysis, macrophage also activate proteases involved in coagulation. Therefore, the elaboration of procoagulant activity by macrophage-derived foam cells will be determined. Utilizing these parameters, the relationship the cell's state of activation and its subsequent response to lipid and/or lipoprotein accumulation will be investigated. Finally, the effect of soluble foam cell factors on a variety of endothelial and smooth muscle cell properties important to vascular homeostasis will be investigated. These include plasminogen activator/inhibitor activities, release of collagenase, degradation of cell-derived matrix, expression of procoagulant activity and reactivity to monocytes. Elucidation of how macrophage-derived foam cells may directly or indirectly contribute to or modulate these processes by other cells will contribute significantly to our understanding of lesion progression.
