Our extensive preliminary work has generated the unexpected hypothesis that the well-established apoptotic effect of transforming growth factor-beta 1 (TGF-b1) on endothelial cells is mediated by endogenous vascular endothelial growth factor (VEGF). This conclusion is based on our findings that TGF-b1 stimulates endothelial cell expression of VEGF and that monoclonal antibodies to VEGF block TGF-b1-induced apoptosis. Because apoptosis is an essential component of vessel formation, this novel mechanism of endothelial cell apoptosis may have an important role in angiogenesis and vasculogenesis. We therefore propose: 1. To characterize the VEGF receptor(s) and downstream signaling pathways through which endogenous VEGF mediates the apoptotic activity of TGF-b1 on endothelial cells. We will investigate signal transduction pathways activated by endogenous VEGF in response to TGF-b1 treatment, and potential cross-talk between VEGF- and TGF-b1-specific pathways. The use of synthetic inhibitors and dominant negative mutants will afford the identification of the signaling pathway(s) that mediate TGF-b1 apoptotic signal(s). 2. To study the role of VEGF-mediated apoptosis in angiogenesis and vasculogenesis in vitro and in vivo. TGF-b1 induces both apoptosis and vessel formation. Based on our preliminary work, we hypothesize that the angiogenic and vasculogenic activities of TGF-b1 are mediated by VEGF with an autocrine mechanism. We propose to test our hypothesis using in vitro and in vivo models of angiogenesis and vasculogenesis. The results will elucidate the mechanisms through which vessel formation is controlled by the interplay of VEGF and TGF-b1, two potent angiogenesis inducers. A detailed understanding of the mechanisms through which VEGF and TGF-b1 interact can have important implications for the development of pharmacological treatments aimed at the control of angiogenesis.
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