The chemokine receptor CX3CR1 has recently been identified in animal and human studies to be an important molecule in the pathogenesis of coronary artery disease (CAD) and in internal carotid artery (ICA) occlusive disease. CX3CR1 is known to be expressed by effector leukocytes including monocytes, and its ligand fractalkine (FKN, CX3CL1) is expressed by activated endothelium. Thus, it has been postulated that the CX3CR1 effect is mediated through monocytes. However, this is far from clear as it has now been found that vascular smooth muscle cells (VSMC) also express CX3CR1 and proliferate and migrate in response to CX3CL1. CX3CR1 is not only capable of transducing signals that stimulate G proteins, downstream pathways and chemotaxis, but it has remarkable cell adhesion properties that allow CX3CR1-expressing cells to be captured by FKN-expressing endothelium under physiologic flow conditions. CX3CR1 is polymorphic in man and the M280 polymorphism which is associated with protection from CAD and from ICA occlusive disease results in defective cell adhesion. Thus, many groups have postulated that the mechanism of CX3CR1 involvement in atherogenesis is due to the adhesive effects of FKN-CX3CR1 promoting monocyte trafficking into the vessel wall. However, this mechanism has not been proven. The recent identification of VSMC proliferation in response to CX3CR1 activation, and CX3CR1 function in other cell types such as epithelium provides evidence for the possible importance of CX3CR1 signaling in inflammatory responses such as atherogenesis. While the mechanism of CX3CR1 activity in CAD and ICA occlusive disease is not clear, it has become an attractive therapeutic target for preventing these diseases. We hypothesize that CX3CR1 affects the activity of both monocytes and vascular smooth muscle cells which act in concert to produce the atherosclerotic plaque. To achieve our goal of identifying the mechanisms by which CX3CR1 regulates atherosclerotic plaque formation, we aim to study CX3CR1-deficient mice and mice expressing mutated CX3CR1 isoforms that are singly defective in cell adhesion or signal transduction. ? ? ?
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