Platelet-activating factor enhances vascular endothelial growth factor-induced endothelial cell motility and neoangiogenesis in a murine matrigel model

We previously reported that platelet-activating factor (PAF) enhances the a ngiogenic activity of certain polypeptide mediators such as tumor necrosis factor and hepatocyte growth factor by promoting endothelial cell motility. The purpose of the present study was to evaluate whether the synthesis of PAF induced by vascular endothelial growth factor (VEGF) might affect endot helial cell motility, microvascular permeability, and angiogenesis. The neo angiogenesis and synthesis of PAF induced by VEGF were studied in vivo in a murine Matrigel model, Dermal permeability was studied in mice by injectio n of I-125-albumin. The synthesis of PAF, cell motility, and the increased I-125-albumin transfer across endothelial monolayers were studied in vitro by using cultures of human umbilical cord vein-derived endothelial cells (H UVECs). The results obtained demonstrate that the neoangiogenesis induced b y VEGF in vivo was associated with a local synthesis of PAF and was inhibit ed by WEB2170 and CV3988, 2 chemically unrelated, specific PAF-receptor ant agonists. In contrast, WEB2170 did not inhibit VEGF-enhanced dermal permeab ility, suggesting that the latter was independent of the synthesis of PAF, In vitro, it was found that VEGF induced the synthesis of PAF by HUVECs in a dose- and time-dependent manner. The cell motility induced by VEGF was in hibited by PAF-receptor antagonists. In contrast, VEGF-induced proliferatio n of HUVECs and albumin transfer through HUVEC monolayer were unaffected by PAF-receptor antagonists. These results suggest that the synthesis of PAF induced by VEGF enhances endothelial cell migration and contributes to the angiogenic effect of VEGF in the in vivo Matrigel model.