Tissue factor pathway inhibitor blocks angiogenesis via its carboxyl terminus.
OBJECTIVE
Tissue factor pathway inhibitor (TFPI) is the primary regulator of the tissue factor (TF) coagulation pathway. As such, TFPI may regulate the proangiogenic effects of TF. TFPI may also affect angiogenesis independently of TF, through sequences within its polybasic carboxyl terminus (TFPI C terminus [TFPIct]). We aimed to determine the effects of TFPI on angiogenesis and the role of TFPIct.


RESULTS
Transgenic overexpression of TFPI attenuated angiogenesis in the murine hindlimb ischemia model and an aortic sprout assay. In vitro, TFPI inhibited endothelial cell migration. Peptides within the human TFPIct inhibited endothelial cell cord formation and migration in response to vascular endothelial growth factor (VEGF) 165 but not VEGF121. Furthermore, exposure to human TFPIct inhibited the phosphorylation of VEGF receptor 2 at residue Lys951, a residue known to be critical for endothelial cell migration. Finally, systemic delivery of a murine TFPIct peptide inhibited angiogenesis in the hindlimb model.


CONCLUSIONS
These data demonstrate an inhibitory role for TFPI in angiogenesis that is, in part, mediated through peptides within its carboxyl terminus. In addition to its known role as a TF antagonist, TFPI, via its carboxyl terminus, may regulate angiogenesis by directly blocking VEGF receptor 2 activation and attenuating the migratory capacity of endothelial cells.
Division of Cardiovascular Diseases, Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
Eric W
EW
Holroyd
Sinny
S
Delacroix
Katarina
K
Larsen
Adriana
A
Harbuzariu
Peter J
PJ
Psaltis
Ling
L
Wang
Shuchong
S
Pan
Thomas A
TA
White
Tyra A
TA
Witt
Laurel S
LS
Kleppe
Cheryl S
CS
Mueske
Debabrata
D
Mukhopadhyay
Robert D
RD
Simari
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002465:Cell Movement; D004195:Disease Models, Animal; D006493:Heparin / Q000378:metabolism; D006614:Hindlimb; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008074:Lipoproteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D008074:Lipoproteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D010455:Peptides; C058992:Tagln protein, mouse; C051928:lipoprotein-associated coagulation inhibitor; D006493:Heparin; D040301:Vascular Endothelial Growth Factor Receptor-2