Placenta growth factor stimulates MAP kinase and mitogenicity but not phospholipase C-γ and migration of endothelial cells expressing Flt 1

Vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) are structurally related growth factors for endothelial cells. VEGF binds to the related receptor tyrosine kinases Fit 1 and KDR/Flk 1 with high affinity, whereas PlGF binds only to Fit 1. Ligand-stimulated KDR is known to transduce signals for cellular activity such as proliferation and migration, whereas weak or no responses have been recorded for Fit 1. We examined VEGF and PIGF for their capacity to stimulate signal transduction in porcine aortic endothelial cells expressing Fit 1 or KDR. VEGF had essentially no effect on Fit 1 expressing cells, but induced DNA synthesis and migration of KDR expressing cells. PlGF on the other hand induced DNA synthesis but not migration of the Fit 1 cells. In agreement, MAP kinase, examined as a marker for DNA synthesis, was activated both by VEGF-stimulation of the KDR cells and by PlGF-stimulation of the Fit 1 cells. In contrast, phospholipase C-gamma (PLC-gamma), was tyrosine phosphorylated only in VEGF stimulated KDR cells, and not in the PlGF-stimulated Fit 1 cells, which is in agreement with a role for PLC-gamma in cellular migration. We furthermore examined induction of protein levels of plasminogen activator (PA), which was evident in the PlGF-stimulated Fit 1 cells, but not in the VEGF-stimulated KDR cells. These data show that Fit 1 is able to mediate an array-of biological signals when appropriately stimulated and that the pattern of responses of PlGF-stimulation of Fit 1 is distinct from the pattern of responses to VEGF-stimulation of KDR.