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Background  The fusion protein VEGF 121 /rGel composed of the growth factor VEGF 121  and the plant toxin gelonin targets the tumor neovasculature and exerts impressive anti-vascular effects. We have previously shown that VEGF 121 /rGel is cytotoxic to endothelial cells overexpressing VEGFR-2 but not to endothelial cells overexpressing VEGFR-1. In this study, we examined the basis for the specific toxicity of this construct and assessed its intracellular effects  in vitro  and  in vivo .    Methods  We investigated the binding, cytotoxicity and internalization profile of VEGF 121 /rGel on endothelial cells expressing VEGFR-1 or VEGFR-2, identified its effects on angiogenesis models  in vitro  and  ex vivo , and explored its intracellular effects on a number of molecular pathways using microarray analysis.    Results  Incubation of PAE/VEGFR-2 and PAE/VEGFR-1 cells with  125 I-VEGF 121 /rGel demonstrated binding specificity that was competed with unlabeled VEGF 121 /rGel but not with unlabeled gelonin. Assessment of the effect of VEGF 121 /rGel on blocking tube formation  in vitro  revealed a 100-fold difference in IC 50  levels between PAE/VEGFR-2 (1 nM) and PAE/VEGFR-1 (100 nM) cells. VEGF 121 /rGel entered PAE/VEGFR-2 cells within one hour of treatment but was not detected in PAE/VEGFR-1 cells up to 24 hours after treatment. In vascularization studies using chicken chorioallantoic membranes, 1 nM VEGF 121 /rGel completely inhibited bFGF-stimulated neovascular growth. The cytotoxic effects of VEGF 121 /rGel were not apoptotic since treated cells were TUNEL-negative with no evidence of PARP cleavage or alteration in the protein levels of select apoptotic markers. Microarray analysis of VEGF 121 /rGel-treated HUVECs revealed the upregulation of a unique "fingerprint" profile of 22 genes that control cell adhesion, apoptosis, transcription regulation, chemotaxis, and inflammatory response.    Conclusions  Taken together, these data confirm the selectivity of VEGF 121 /rGel for VEGFR-2-overexpressing endothelial cells and represent the first analysis of genes governing intoxication of mammalian endothelial cells by a gelonin-based targeted therapeutic agent.

Cytotoxicity of VEGF121/rGel on vascular endothelial cells resulting in inhibition of angiogenesis is mediated via VEGFR-2