Abstract

Embryo implantation is a complex process that involves interactions between cell surface and extracellular components of the embryo and uterus. Previous studies have shown that heparan sulfate proteoglycans (HSPGs) and heparan sulfate (HS)-binding proteins play a role in embryo implantation. HS-binding proteins include Heparin/HS Interacting Protein (HIP/RPL29) and growth factors including fibroblast growth factor 2 (FGF-2), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and heparin-binding epidermal growth factor (HB-EGF). HS-binding growth factors present in the extracellular matrix (ECM) can be released by ECM degrading enzymes, including heparanase (HPSE), an endo-β-D-glucuronidase. Previous studies have shown that HPSE is present in invasive human trophoblasts. Exogenous added HPSE was shown to improve embryo implantation in mice. Previous studies demonstrated that a synthetic peptide of HIP/RPL29 and HPSE recognize common sequences on HS. This HIP/RPL29 peptide has been shown to inhibit HPSE activity. HIP/RPL29, HSPGs, and HS-binding growth factors are present at the implantation site and play important roles during embryo implantation. Therefore, I chose to study the interplay between these molecules in the presence of the HS-modifying enzyme, heparanase.

In this dissertation, I demonstrate the expression of heparanase during pregnancy in mice, baboon, and humans. I also demonstrate HIP/RPL29's effect on HS-binding growth factor responses in endothelial cells. The studies in this dissertation establish that heparanase is an important player during embryo implantation and that HIP/RPL29 can modulate certain HS-binding growth factor responses in endothelial cells.