Specific components of the extracellular matrix (ECM) accumulate in atherosclerosis and promote the inflammatory phase of vascular disease. We have focused on two of these components, hyaluronan and versican, which interact with each other to form higher ordered molecular complexes and not only contribute to ECM expansion during the development of vascular disease but also have a dramatic effect influencing the phenotype of arterial smooth muscle cells. Recently, we found that an ECM enriched in hyaluronan and versican promotes the adhesion of monocytes in a hyaluronan dependent manner suggesting that these specific ECM components may form part of what could be considered a pro-inflammatory ECM. These observations have led us to hypothesize that hyaluronan and versican are produced by vascular cells in response to specific inflammatory stimuli and contribute to the formation of an ECM that binds monocytes. We further hypothesize that monocyte/macrophage also synthesize these ECM components in response to inflammatory stimuli and degrade hyaluronan and versican and that a balance between these two activities partially regulates the phenotype of the monocyte/macrophage. To test this hypothesis, we will have 4 specific Aims.
In Aim 1, we will identify the full nature of this specialized ECM and test the requirements for these components for these components in hyaluronan-dependent monocyte adhesion.
In Aim 2, we will explore the role that hyperlipidemia and modified lipids play in the generation of this ECM and define the changes in versican and hyaluronan during the development of atherosclerosis.
Aim 3 will focus on the synthesis and degradation of versican and hyaluronan by the monocyte/macrophage and the impact of these ECM components monocyte/macrophage proliferation, adhesion and migration.
In Aim 4, we will test the importance of this hyaluronan based ECM in the generation of both early and late atherosclerotic lesions by using mouse models of atherosclerosis susceptibility and animals in which specific genes required for the assembly of this ECM have been ablated.
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