Tissue factor pathway inhibitor inhibits endothelial cell proliferation via association with the very low density lipoprotein receptor

Tissue factor pathway inhibitor (TFPI) contains three Kunitz-type proteinas e inhibitor domains and is a potent inhibitor of tissue factor-mediated coa gulation. Here, we report that TFPI inhibits the proliferation of basic fib roblast growth factor-stimulated endothelial cells. A truncated form of TFP I, containing only the first two Kunitz-type proteinase inhibitor domains, has very little antiproliferative activity, suggesting that the carboxyl-te rminal region of TFPI is responsible for this activity. Binding studies rev ealed that full-length TFPI, but not the truncated TFPI molecule, is recogn ized by the very low density lipoprotein receptor (VLDL receptor) indicatin g that this receptor is a novel high affinity endothelial cell receptor for TFPI. The antiproliferative activity of TFPI on endothelial cells is inhib ited by the receptor-associated protein, a known antagonist of ligand bindi ng by the VLDL receptor, and by anti-VLDL receptor antibodies. These result s confirm that the antiproliferative activity of TFPI is mediated by the VL DL receptor and suggest that this receptor-ligand system may be a useful ta rget for the development of new antiangiogenic and antitumor agents.