Vascular remodeling is a complex process involving endothelial cell injury/dysfunction which affects vascular wall smooth muscle cell proliferation, hypertrophy, migration and metabolism, and is a contributor to the pathogenesis of disorders such as hypertension, atherosclerosis and restenosis. However, the cellular and molecular mechanisms of vascular remodeling are not well understood. We propose an integrated study using static and hemodynamic 3-dimensional models with normal vascular cell lines and those that we have isolated from salt sensitive hypertensive rats, that mimics the architecture of the vascular wall and also provide its physical environment. This approach will allow to address the hypothesis that the combination of atherogenic levels of LDL and hemodynamic forces include cellular and molecular changes in vascular cells by inducing mechanotransduction mechanisms for the blood vessel wall that result in vascular remodeling. We will use selected end-points (morphological phenotype, cell shape and area, cell proliferation and gene expression), which have been reported as characteristic vascular cell changes during the remodeling process. To address this hypothesis, we propose the following specific aims: 1) Assess changes in morphological phenotype, cytoskeleton arrangement, mitogenic labeling and permeability through the endothelial layer when the 3-D vascular cell co-culture models are treated or not treated with high levels of LDL; 2) Measure temporal changes in the expression of early response genes (c-myc and c-fos), growth factors (PDGF and TGF/beta), extracellular matrix proteins (laminin and collagen III) and NO synthase following treatment of cultures with LDL; 3) Using inhibitors, assess the role of calcium, protein kinases and MAP-kinase in the early signaling mechanisms mediating the effects of LDL on vascular cells using the two models. The proposed studies will provide insight into the mechanism by which atherogenic levels of LDL alter the morphological and functional phenotypes of hypertension-modified endothelial and smooth muscle cells. The long term goal of the proposed studies is to provide a better understanding of the temporal sequence of events (and signaling) involved in the early period of vascular remodeling. The knowledge gained will suggest strategies for developing the best therapies for treatment of different vascular disorders.
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