The long standing goal of this research project is to provide insights into lipid transport-independent mechanisms by which apolipoprotein E (apo E) protects against vascular occlusive diseases. The past funding period has documented apoE protection against exacerbated neointimal hyperplasia after endothelial denudation injury of the arteries, via mechanisms related to apoE inhibition of smooth muscle cell migration and proliferation, and excessive extracellular matrix deposition. The current study will expand on these findings and will test the overall hypothesis that the vascular protective effects of apoE are mediated via its binding to various cell surface proteins receptors on smooth muscle cells, each activating distinct signaling pathways that result in inhibition of growth factor-induced cell migration, proliferation, and excessive extracellular matrix deposition.
Specific Aim 1 will use genetically modified mice to test the hypothesis that apoE interaction with LRP-1, heparan sulfate proteoglycans (HSPG), and apoE receptor-2 (apoER2) on smooth muscle cells inhibits migration, proliferation, and excessive matrix deposition, respectively, and these events are all necessary in combination to prevent neointimal formation after endothelial denudation.
Specific Aim 2 will identify cell signaling mechanism(s) by which apoE binding to LRP-1 inhibits growth factor-induced smooth muscle cell migration. The hypothesis is that apoE binding to LRP-1 inhibits cell migration via stimulation of adenylate cyclase and/or inhibition of phosphodiesterases.
Specific Aim 3 will examine the mechanism by which apoER2 modulates extracellular matrix deposition after arterial injury and to determine if apoE binding to apoER2 is involved with this regulation.
Specific Aim 4 will identify the HSPG on the cell surface that is responsible for mediating apoE-induced cell signaling events that are required to inhibit smooth muscle cell proliferation. Antisense oligonucleotides will be employed to suppress expression of specific proteoglycan core proteins to assess their respective role in mediating early events associated with apoE inhibition of smooth muscle cell proliferation. Understanding the pleiotropic mechanisms by which apoE inhibits neointimal hyperplasia will contribute to our understanding of the overall pathogenic mechanisms of neointimal hyperplasia and vasuclar occlusion. This information will be valuable in designing strategy to limit vascular occlusion due to naturally occurring atherosclerosis and/or restenosis. ? ?
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