? We postulate that oxidized lipids, as well as local mechanical stress regulate the expression and shedding of syndecan-1 and -4 as an initial adaptive response that ultimately contributes to the generation of a sustained proinflammatory, growth-stimulating environment that leads to vascular lesion formation. In particular, we speculate that syndecans shed in response to these pro-inflammatory stimuli will preferentially bind and effectively sequester chemokines and proteases relevant to vascular lesion formation. Specifically, we plan to (1) Determine the capacity of arterial wall mechanics and oxidized lipids, both as isolated and interactive factors, to modulate syndecan expression and shedding. The expression of syndecan- 1 and -4 will be characterized in hypertensive ApoE deficient mice using immunohistochemical and in situ hybridization techniques. Moreover, correlative in vitro studies will be performed to determine the capacity of cyclic mechanical stress and oxidized lipids, both as isolated and interactive factors, to potentiate syndecan expression and shedding in vascular smooth muscle cells and periadventitial fibroblasts. (2) Characterize the signal transduction pathways activated by mechanical stress and oxidized lipids that converge in regulating syndecan expression and shedding. The extents to which redox-sensitive and insensitive MAP kinase signaling pathways initiated in response to mechanical stress and oxidized lipids converge in regulating syndecan shedding and expression will be determined. Furthermore, the potential that unique pathways differentially regulate syndecan expression and shedding will be investigated and the role of metalloproteinases as primary mediators of accelerated syndecan shedding in vascular mesenchymal cells will be defined. (3) Define the molecular binding interactions between shed syndecans and selected proatherogenic chemokines and proteases. The relative binding affinities of selected chemokines (RANTES, MCP-1) and proteases (MMP-2, MMP-9) to syndecan associated heparan sulfate chains shed in response to oxidized lipids and/or mechanical stress will be characterized and the susceptibility of the complexed protein to degradation will be defined. This data will facilitate subsequent studies directed at assessing the capacity of pharmacological inhibitors of heparan and chondroitin sulfate, as well as syndecan shedding to limit the formation of pro-inflammatory or proteolytically active solid phase gradients in vitro and in vivo. ? ?
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