Macrophage(MO)-colony stimulating factor (M-CSF) importantly contributes to the development of atherosclerotic lesions. We have found that the absence of M-CSF in atherosclerosis-prone apolipoprotein (apo) E or low-density lipoprotein receptor (LDLR)- deficient mice results in substantially reduced atherosclerosis despite augmented hypercholesterolemia. Our most recent studies provide compelling evidence in favor of a direct local effect of M-CSF within the vessel wall. These advances, together with the characterization of the M-CSF-mediated induction of urokinase plasminogen activator (uPA) and matrix metalloproteinases (MMPs) cascade have prompted more refined questions on the molecular mechanisms responsible for the full range of M-CSF actions in the diseased vessel wall. In this proposal, we seek to extend our research efforts to understand the role of M-CSF in the development and disruption of arterial lesions by testing following three hypotheses: 1) pleiotropic effects of M-CSF on intimal MO and SMC are modulated mainly through the activation of nuclear factors downstream to the Ras-mediated cell signaling pathways. One such factor is the transcription factor Ets-2 that promotes cell proliferation and survival, 2) increased M-CSF activity in atherosclerotic lesions contributes to the MO -mediated matrix remodeling by up regulating the expression of uPA and MT3-MMP genes. This effect of M-CSF may play a role in plaque disruption, and 3) M-CSF up regulates the MO-specific transcription of uPA and MT3-MMP genes by activating a common set of trans-acting factors (such as Ets family of transcription factors) that form ternary complexes with AP-l and bind to cis-acting DNA elements present in the 5' regulatory region of these genes.
The specific aims are: 1) to investigate the effects of M-CSF on the growth of arterial lesion-associated cells in vivo using mice lacking M-CSF and/or apoE and to perform in vitro studies using cultured cells from M-CSF-deficient mice to determine the mechanism(s) underlying the M-CSF mediated proliferation and survival of MO and SMC, 2) to determine the effects of M-CSF on the expression of uPA and MT3-MMP in cultured MO and to examine the association of M-CSF regulated production of uPA and MT3-MMP to alterations in the character of atherosclerotic lesions, and 3) to identify the cis-acting elements in the uPA and MT3-MMP promoters that mediate the inductive effects of M-CSF on the expression of these genes and to examine the signaling events connecting M-CSF with the nuclear regulators of uPA and MT3-MMP. We believe our studies will provide new and important information regarding the role of M-CSF in the development and disruption of atherosclerotic and proliferative vascular lesions and this information may prove useful in design of novel therapeutic interventions for vascular diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Pathology A Study Section (PTHA)
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Srinivas, Pothur R
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Cedars-Sinai Medical Center
Los Angeles
United States
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