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Background  Vascular endothelial growth factor (VEGF) is taken up by parasitized red blood cells during malaria and stimulates intra-erythrocytic growth of  Plasmodium falciparum in vitro . The cause and consequence of this uptake is not understood.    Methods   Plasmodium falciparum  was cultured  in vitro.  Parasite growth and intracellular VEGF levels were assessed using flow cytometry. Intracellular VEGF was visualized by fluorescence immunocytochemistry. Phosphorylated tyrosine was measured by western blotting.  In vivo  assessment of intra-erythrocytic VEGF was performed in  Plasmodium berghei  ANKA-infected C57BL/6 mice.    Results  VEGF accumulated intracellularly in infected red blood cells, particularly in schizonts.  In vitro  growth of  P. falciparum  was unchanged when co-cultured with the anti-VEGF antibody bevacizumab or with an anti-VEGF receptor-1 peptide. In contrast, the VEGF receptor-2 inhibitor, SU5416, dose-dependently inhibited growth. None of the treatments reduced intracellular VEGF levels. Thus, the anti-parasitic effect of SU5416 seemed independent of VEGF uptake. SU5416 reduced phosphorylated tyrosine in parasitized red blood cells. Similarly, the broad-spectrum tyrosine kinase inhibitor genistein dose-dependently inhibited  P. falciparum  growth and reduced tyrosine phosphorylation. Neither bevacizumab nor anti-VEGF receptor-1 peptide affected tyrosine kinase activity. Finally,  in vivo  uptake of VEGF in  P. berghei  ANKA was demonstrated, analogous to the  in vitro  uptake in  P. falciparum,  making it a possible model for the effects of VEGF signalling  in vivo  during malaria.    Conclusions  Inhibition of VEGFR-2 signalling reduces intra-erythrocytic growth of  P. falciparum,  likely due to tyrosine kinase inhibition. Internalisation of VEGF in  P. falciparum- infected red blood cells does not rely on VEGF receptors. The function of  in vivo  uptake of VEGF can be studied in rodent malaria models.

Effects of the vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor SU5416 on in vitro cultures of Plasmodium falciparum