VEGF and TGF-1 are potent angiogenesis inducers with opposing effects on endothelial cells. TGF-1 induces apoptosis; VEGF protects endothelial cells from apoptosis. We found that TGF-1 promotes endothelial cell expression of FGF-2, which up-regulates VEGF synthesis. Inhibition of VEGF signaling through VEGF receptor 2 (flk-1) abrogates TGF-1-induced apoptosis and p38 MAPK activation. Inhibition of p38 MAPK blocks TGF-1-induced apoptosis, showing that VEGF͞flk-1-mediated activation of p38 MAPK is required for TGF-1 induction of apoptosis. In the absence of TGF-1, VEGF activates p38 MAPK and promotes endothelial cell survival. However, in context with TGF-1, VEGF͞flk-1-mediated activation of p38 MAPK results in apoptosis. Thus, cross-talk between TGF-1 and VEGF signaling converts VEGF͞flk-1-activated p38 MAPK into a proapoptotic signal. This finding illustrates an unexpected role of VEGF and indicates that VEGF can be pharmacologically converted into an apoptotic factor, a novel approach to antiangiogenesis therapy.angiogenesis ͉ MAPK kinase ͉ p38 ͉ VEGF receptor ͉ cancer