Signals leading to apoptosis-dependent inhibition of neovascularization bythrombospondin-1

Thrombospondin-1 (TSP-1) is a naturally occurring inhibitor of angiogenesis that limits vessel density in normal tissues and curtails tumor growth. He re, we show that the inhibition of angiogenesis in vitro and in vivo and th e induction of apoptosis by thrombospondin-1 all required the sequential ac tivation of CD36, p59(fyn), caspase-3 like proteases and p38 mitogen-activa ted protein kinases. We also detected increased endothelial cell apoptosis in situ at the margins of tumors in mice treated with thrombospondin-1. The se results indicate that thrombospondin-1, and possibly other broad-spectru m natural inhibitors of angiogenesis, act in vivo by inducing receptor-medi ated apoptosis in activated microvascular endothelial cells.