Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway

Thrombospondin-1 (TSP1) is a potent natural inhibitor of angiogenesis. Alth ough TSP1 has been reported to induce endothelial cell apoptosis in vitro a nd to downregulate neovascularization in vivo, the molecular mechanisms tha t link these two processes have yet to be established. Here we report that TSP1 mediates endothelial cell apoptosis and inhibits angiogenesis in assoc iation with increased expression of Bar, decreased expression of Bcl-2, and processing of caspase-3 into smaller proapoptotic forms. The ability of TS P1 to induce both endothelial cell apoptosis in vitro and to suppress angio genesis in vivo was blocked by the caspase-3 inhibitor z-DEVD-FMK. TSP1 als o attenuated VEGF-mediated Bcl-2 expression in endothelial cells in vitro a nd angiogenesis in vivo. Furthermore, TSP1 induced endothelial cell apoptos is and inhibited neovascularization in sponge implants in SCID mice. We con clude that TSP1 induces endothelial cell apoptosis and inhibits neovascular ization by altering the profile of survival gene expression and activating caspase-3. Copyright (C) 2000 S. Karger AG. Basel.