Endothelial-derived tissue factor pathway inhibitor regulates arterial thrombosis but is not required for development or hemostasis.
The antithrombotic surface of endothelium is regulated in a coordinated manner. Tissue factor pathway inhibitor (TFPI) localized at the endothelial cell surface regulates the production of FXa by inhibiting the TF/VIIa complex. Systemic homozygotic deletion of the first Kunitz (K1) domain of TFPI results in intrauterine lethality in mice. Here we define the cellular sources of TFPI and their role in development, hemostasis, and thrombosis using TFPI conditional knockout mice. We used a Cre-lox strategy and generated mice with a floxed exon 4 (TFPI(Flox)) which encodes for the TFPI-K1 domain. Mice bred into Tie2-Cre and LysM-Cre lines to delete TFPI-K1 in endothelial (TFPI(Tie2)) and myelomonocytic (TFPI(LysM)) cells resulted in viable and fertile offspring. Plasma TFPI activity was reduced in the TFPI(Tie2) (71% ± 0.9%, P < .001) and TFPI(LysM) (19% ± 0.6%, P < .001) compared with TFPI(Flox) littermate controls. Tail and cuticle bleeding were unaffected. However, TFPI(Tie2) mice but not TFPI(LysM) mice had increased ferric chloride-induced arterial thrombosis. Taken together, the data reveal distinct roles for endothelial- and myelomonocytic-derived TFPI.
White
Thomas A
TA
Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Johnson
Tucker
T
Zarzhevsky
Natalia
N
Tom
Cindy
C
Delacroix
Sinny
S
Holroyd
Eric W
EW
Maroney
Susan A
SA
Singh
Ripudamanjit
R
Pan
Shuchong
S
Fay
William P
WP
van Deursen
Jan
J
Mast
Alan E
AE
Sandhu
Gurpreet S
GS
Simari
Robert D
RD
D000818:Animals; D001158:Arteries / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D006487:Hemostasis; D053208:Kaplan-Meier Estimate; D008074:Lipoproteins / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2; D013927:Thrombosis / Q000097:blood* / Q000378:metabolism
D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse