EICOSAPENTAENOIC ACID ATTENUATES VASCULAR ENDOTHELIAL GROWTH FACTOR-INDUCED PROLIFERATION VIA INHIBITING FLK-1 RECEPTOR EXPRESSION IN BOVINE CAROTID-ARTERY ENDOTHELIAL-CELLS

Eicosapentaenoic acid (EPA; 20:5, n-3) can restrain tumor growth and m etastasis in vivo; however, the mechanism of its antitumor effect is s till not fully understood. Angiogenesis is a crucial process for tumor growth and metastasis and inhibition of tu mor angiogenesis can suppr ess tumor growth and metastasis in vivo. Vascular endothelial growth f actor (VECF) is an important angiogenic factor. In this study, we inve stigated the mechanisms of the inhibitory effect of EPA on VEGF-induce d proliferation of bovine carotid artery endothelial (BAE) cells. BAE cells, treated with 0-5 mu g/ml EPA for 48 h, displayed a dose-depende nt suppression to VEGF: (0.2 nM)-induced proliferation. Similar inhibi tory effect was not found in BAE cells treated with arachidonic acid ( AA; 20:4, n-6), or docasahexaenoic acid (DHA; 22:5, n-3). In contrast to its effect on VEGF-induced proliferation, EPA had no inhibition to basic fibroblast growth factor (bFGF, 0.2 nM)-induced proliferation in BAE cells. Both VEGF and bFGF activated mitogen-activated protein (MA P) kinase in BAE cells; however, EPA selectively inhibited VEGF-induce d, but not bFGF-induced activation of MAP kinase. Flk-1 expression was inhibited dose-dependently in EPA-treated cells, whereas Flt-1 expres sion was increased in EPA treated cells. This in vitro inhibitory effe ct by EPA on Flk-1 receptor expression provides indirect evidence that one of the mechanisms of EPA for antitumor action in vivo maybe relat ed to its antiangiogenic action. (C) 1998 Wiley-Liss, Inc.