Heterodimers of placenta growth factor vascular endothelial growth factor - Endothelial activity, tumor cell expression, and high affinity binding to Flk-1/KDR

Here we show that the Escherichia coli expressed monomers of placenta growth factor (PLGF)(129) and vascular endothelial growth factor (VEGF)(165) can be refolded in vitro to form PLGF/VEGF heterodimers. The purified recombinant PLGF/VEGF heterodimers and VEGF homodimers have potent mitogenic and chemotactic effects on endothelial cells. However, PLGF/VEGF heterodimers display 2050-fold less mitogenic activity than VEGF(165) homodimers. In contrast, PLGF(129) homodimers have little or no effect in these in vitro assays. We also demonstrate the presence of natural PLGF/VEGF heterodimers in the conditioned media of various human tumor cell lines. While PLGF/VEGF heterodimers bind with high affinity to a soluble Flk-1/KDR receptor, PLGF(129) homodimers fail to bind to this receptor, Cross-linking of I-125-ligands to human umbilical vein endothelial cells reveals that PLGF/VEGF heterodimers and VEGF(165) homodimers, but not PLGF(129) homodimers, form complexes with membrane receptors. VEGF(165) homodimers and PLGF/VEGF heterodimers stimulate tyrosine phosphorylation of a 220-kDa protein, the expected size for the KDR receptor in human umbilical vein endothelial cells, whereas PLGF(129) homodimers are unable to induce tyrosine phosphorylation of this protein, These data indicate that PLGF may modulate VEGF-induced angiogenesis by the formation of PLGF/VEGF heterodimers in cells producing both factors.