A balance between tissue factor and tissue factor pathway inhibitor is required for embryonic development and hemostasis in adult mice.
Inactivation of the murine tissue factor (TF) gene or tissue factor pathway inhibitor 1 (TFPI) gene results in embryonic lethality, indicating that both are required for embryonic development. We have shown that expression of low levels of TF from a transgene (hTF) rescues TF-null embryos. However, low-TF mice (mTF(-/-)/hTF+) have hemostatic defects in the uterus, placenta, heart, and lung. In this study, we hypothesized that the death of TFPI-/- embryos was due to unregulated TF/FVIIa activity and that the hemostatic defects in low-TF mice were due to insufficient TF expression. Therefore, we attempted to rescue TFPI-/- embryos by reducing TF expression, and to restore hemostasis in low-TF mice by abolishing TFPI expression. Intercrossing TFPI(+/-)/mTF(+/-)/hTF+/- mice generated close to the expected number of TFPI(-/-)/low-TF mice at weaning age from 128 offspring, indicating rescue of TFPI-/- embryos from embryonic lethality. Conversely, a decrease in TFPI levels dose-dependently prolonged the survival of low-TF mice and rescued the hemorrhagic defects in the lung and placenta but not in the heart or uterus. These results indicate that the correct balance between TF and TFPI in different organs is required to maintain hemostasis during embryonic development and in adult mice.
Pedersen
Brian
B
Department of Immunology, The Scripps Research Institute, 10550 N Torrey Pines Rd, CVN-18, La Jolla, CA 92037, USA.
Holscher
Todd
T
Sato
Yuichiro
Y
Pawlinski
Rafal
R
Mackman
Nigel
N
D000367:Age Factors; D000818:Animals; D003326:Coronary Circulation; D047108:Embryonic Development / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology; D006470:Hemorrhage / Q000401:mortality / Q000503:physiopathology; D006487:Hemostasis / Q000502:physiology*; D008074:Lipoproteins / Q000235:genetics* / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010920:Placenta / Q000502:physiology; D011247:Pregnancy; D011652:Pulmonary Circulation; D012333:RNA, Messenger / Q000032:analysis; D015996:Survival Rate; D013925:Thromboplastin / Q000235:genetics* / Q000378:metabolism*; D014599:Uterus / Q000098:blood supply
D008074:Lipoproteins; D012333:RNA, Messenger; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin