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 proteinase inhibitor domains and is a potent inhibitor of tissue factor-mediated coagulation. Here, we report that TFPI inhibits the proliferation of basic fibroblast growth factor-stimulated endothelial cells. A truncated form of TFPI, containing only the first two Kunitz-type proteinase inhibitor domains, has very little antiproliferative activity, suggesting that the carboxyl-terminal region of TFPI is responsible for this activity. Binding studies revealed that full-length TFPI, but not the truncated TFPI molecule, is recognized by the very low density lipoprotein receptor (VLDL receptor) indicating that this receptor is a novel high affinity endothelial cell receptor for TFPI. The antiproliferative activity of TFPI on endothelial cells is inhibited by the receptor-associated protein, a known antagonist of ligand binding by the VLDL receptor, and by anti-VLDL receptor antibodies. These results confirm that the antiproliferative activity of TFPI is mediated by the VLDL receptor and suggest that this receptor-ligand system may be a useful target for the development of new anti-angiogenic and antitumor agents.
American Red Cross, Holland Laboratory, Department of Vascular Biology, Rockville, Maryland 20855, USA. toddh@entremed.com
T A
TA
Hembrough
J F
JF
Ruiz
A E
AE
Papathanassiu
S J
SJ
Green
D K
DK
Strickland
D000906:Antibodies / Q000276:immunology; D002455:Cell Division / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008074:Lipoproteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011973:Receptors, LDL / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D008074:Lipoproteins; D011973:Receptors, LDL; C036053:VLDL receptor; C051928:lipoprotein-associated coagulation inhibitor