PLACENTA GROWTH-FACTOR - POTENTIATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR BIOACTIVITY, IN-VITRO AND IN-VIVO, AND HIGH-AFFINITY BINDING TOFLT-1 BUT NOT TO FLK-1 KDR/

The recently identified placenta growth factor (PlGF) is a member of t he vascular endothelial growth factor (VEGF) family of growth factors. PlGF displays a 53% identity with the platelet-derived growth factor- like region of VEGF. By alternative splicing of RNA two PlGF isoforms are generated: PlGF(131) (PlGF-1) and PlGF(152) (PlGF-2). Relative to PlGF(131), PlGF(152) has a 21-amino acid insertion enriched in basic a mino acids. Little is known at the present time about the significance and function of these proteins. To assess their potential role, we cl oned the cDNAs coding for both isoforms, expressed them in mammalian c ells, and purified to apparent homogeneity the recombinant proteins. L ike VEGF, the PlGF isoforms are homodimeric glycoproteins. PlGF(131) i s a non-heparin binding protein, whereas PlGF(152) strongly binds to h eparin. We examined the ability of PlGF to bind to soluble VEGF recept ors, Flt-1 and Flk-1/KDR, and characterized the binding of PlGF to end othelial cells. While the PlGF proteins bound with high affinity to Fl t-1, they failed to bind to Flk-1/KDR. Binding of I-125-PlGF to human endothelial cells revealed two classes of sites, having high and low a ffinity. The high affinity site is consistent with Flt-1; the identity of the low affinity site remains to be determined. Purified PlGF isof orms had little or no direct mitogenic or permeability-enhancing activ ity. However, they were able to significantly potentiate the action of low concentrations of VEGF in vitro and, more strikingly in vivo.