Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1

Angiogenesis is critical for the growth and proliferation of tumors as well as for normal development. We now describe a novel role for histidine-rich glycoprotein (HRGP) in the modulation of angiogenesis. HRGP is a plasma pr otein that circulates in relatively high concentrations (1.5 muM), but has no known function in vivo. We have shown previously that HRGP binds with hi gh affinity to thrombospondin-1 (TSP-1), a homotrimeric glycoprotein that i s a potent inhibitor of angiogenesis. The antiangiogenic activity of TSP-1 is mediated by the binding of properdin-like type I repeats to the receptor CD36. We found that binding of HRGP to TSP-1 was similarly mediated by TSP type I repeats. HRGP colocaIized with TSP-1 in the stroma of human breast cancer specimens, and this interaction masked the antiangiogenic epitope of TSP-1. In assays performed in vitro of endothelial cell migration and tube formation, and in vivo corneal angiogenesis assays, HRGP inhibited the ant iangiogenic effect of TSP-1. These studies suggest that HRGP can modulate t he antiangiogenic activity of TSP-I, and identify a potential mechanism of resistance to the antiangiogenic effect of TSP-1.