Pregnancy-specific Glycoprotein 1 Induces Endothelial Tubulogenesis through Interaction with Cell Surface Proteoglycans

Felipe A Lisboa,James Warren,Gisela Sulkowski,Marta Aparicio,Guido David,Enrique Zudaire,Gabriela S Dveksler

doi:10.1074/jbc.m110.161810

Abstract

Pregnancy-specific β1 glycoproteins (PSGs) are the most abundant fetal proteins in the maternal bloodstream in late pregnancy. They are secreted by the syncytiotrophoblast and are detected around day 14 postfertilization. There are 11 human PSG genes, which encode a family of proteins exhibiting significant conservation at the amino acid level. We and others have proposed that PSGs have an immune modulatory function. In addition, we recently postulated that they are proangiogenic due to their ability to induce the secretion of VEGF-A and the formation of tubes by endothelial cells. The cellular receptor(s) for human PSGs remain unknown. Therefore, we conducted these studies to identify the receptor for PSG1, the highest expressed member of the family. We show that removal of cell surface glycosaminoglycans (GAGs) by enzymatic or chemical treatment of cells or competition with heparin completely inhibited binding of PSG1. In addition, PSG1 did not bind to cells lacking heparan or chondroitin sulfate on their surface, and binding was restored upon transfection with all four syndecans and glypican-1. Importantly, the presence of GAGs on the surface of endothelial cells was required for the ability of PSG1 to induce tube formation. This finding indicates that the PSG1-GAG interaction mediates at least some of the PSG1 proposed functions.

Highlights

Pregnancy-specific ␤1 glycoproteins (PSGs) are the most abundant fetal proteins in the maternal bloodstream in late pregnancy
PSG1 Binds to Cell Surface Proteoglycans—Several cell types derived from different species and tissues, besides the PSG target cells previously identified in our laboratory [14, 17], were tested by FACS for their ability to bind recombinant PSG1
These observations prompted us to investigate whether PSG1 could bind to heparan sulfate proteoglycans which are not expressed by FDC-P1 [23] and have been reported to be absent or expressed at very low levels in several pre-B stage cells [24]

Summary

Introduction

Pregnancy-specific ␤1 glycoproteins (PSGs) are the most abundant fetal proteins in the maternal bloodstream in late pregnancy. Binding to human monocytes (data not shown) and Jurkat cells was reduced to the level of the control protein by growing the cells in medium containing 25 or 50 mM sodium chlorate for 3 days (Fig. 2, G and H).

Results

Conclusion