The overall goal of this research is to understand the etiologic role of macrophage colony-stimulating factor (M-CSF) in atherosclerosis. Accumulating evidence suggests that M-CSF by influencing the recruitment, growth, survival and function of monocyte-macrophages, may contribute importantly to the promotion of atherosclerosis. Supporting this conclusion are this laboratory's recent findings showing that absence of M-CSF in apolipoprotein (apo) E or low density lipoprotein receptor-deficient mice significantly reduces atherosclerosis despite augmented hypercholesterolemia. The mechanism(s) underlying the causal role of M-CSF in atherosclerosis is not known, but may involve specific isoforms of M-CSF whose biological effects are mediated by a single receptor. The overall hypothesis is that augmented expression of tissue associated M-CSF isoforms in response to atherogenic stimuli in the vessel wall and bone marrow plays a critical role in the development of atheromatous lesions. To test aspects of this hypothesis, studies are proposed with the following specific aims: 1) to study the effects of M-CSF deficiency in the vessel wall on the development of arterial lesions by transplanting wild type. bone marrow cells into mice lacking both M-CSF and apoE and to determine by immunological assays which isoforms of M-CSF are expressed by vascular cells in the normal vessel and during atherogenesis in apo-E null mice; 2) to perform in vitro studies using cultured vascular cells from humans and osteopetrotic (op/op) mice to examine the mechanism(s) underlying the M-CSF mediated growth and activation of monocytes and intimal smooth muscle cells; 3) to produce transgenic mice expressing only the mM-CSF isoform on an op/op genetic background and to examine the effects of the mM-CSF on atherogenesis either by feeding the transgenic mice a high fat, high cholesterol diet or by crossing them with apo E-null mice to generate compound mutants expressing mM-CSF on an atherogenic background. These studies may provide new and exciting information that might prove valuable in the rational design of novel therapeutic interventions for atherosclerosis.
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