Modification of heparan sulfate (HS) expression on cell surfaces and in the extracellular matrix (ECM) provides an important pathway for regulation of growth, differentiation, and development of numerous cell types including vascular endothelial and smooth muscle cells. However, little is known about the effects of modulation of heparan sulfate composition on endothelial cell (EC) behavior. In particular, the fellow will study the effect of alterations in expression of HS-carrying proteins which occur during wound healing, inflammation and angiogenesis on composition of the ECM and cell surface HS, to examine the effect of these changes on biological properties of EC, and to identify novel mechanisms responsible for these functional changes. Stable and viral-mediated expression of two key HS-bearing core proteins in ECs (membrane-spanning snydecan-4 and GPI-linked glypican-1) will be employed to examine the effect of increasing cell surface/ECM HS levels on growth, migration and adhesion of ECs. The use of both syndecan and glypican expression constructs allows determination of whether the observed effects are due to a) changes in composition of cell surface/ECM HS chains, b) increased expression of syndecan-4 cytoplasmic tail, and/or c) other specific amino acid sequences in these proteins or others. The goal of this work is to obtain a better understanding of HS control of EC function to better understand angiogenic mechanisms.
