Vascular remodeling can occur in a number of clinical disorders. The remodeling process is the result of a complex set of events resulting in endothelial dysfunction and intimal/medial thickening. The long term objective of these studies is to understand the interactions promoting smooth muscle cell (SMC) migration and proliferation, and increased connective tissue components that result in medial and intimal thickening.
The specific aims of this proposal are to explore the following hypotheses: 1) The migration and proliferation of SMC are regulated by a balance between stimulatory and inhibitory factors released from dysfunctional endothelial cells. Specifically, we propose the following aims to test this hypothesis: assess conditioned medium (CM) from endothelial cell (EC) and SMC cultures, treated with oxidized LDL or subjected to a denudation injury, for effects on SMC migration and proliferation; investigate whether PDGF, bFGF and/or TGFbeta mediate conditioned media effects using neutralizing antibodies. 2) The degree of smooth muscle cell migration in response to soluble factors from dysfunctional EC are modulated by extracellular matrix (ECM) components. Specifically, we propose to examine the CM obtained under Hypothesis 1 using cells cultured on synthetic matrices composed of either laminin, fibronectin, collagen IV or on matrigel. 3) The migration of medial SMC through the vascular wall ECM occurs in part by the combined effects of galaptin and chondroitin sulfate inhibiting the binding of these cells (via the 67 kD laminin/elastin receptor) to laminin. The following aims are proposed: examine the effect of galaptin and chondroitin sulfate on SMC sheet migration and on the binding and migration of SMC on laminin matrices; use antisense oligonucleotide to galaptin mRNA to couple the expression of galaptin to the migratory and proliferative ability of SMC. 4) The migration and proliferation seen in vascular remodeling is mediated through activation of protooncogene dependent pathways. Specifically, the following aims are proposed: measure the expression of c-fos, c-jun and c-myc by EC and SMC following treatment with oxidized LDL or subjected to a denudation injury; use antisense oligonucleotides to the mRNA for c-fos, c-jun and c-myc to couple the expression of these genes to the cellular response. These studies will offer insight into the underlying mechanisms in the vascular remodeling process.
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