Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction.
Plasminogen (Plg)-deficient mice were generated to define the physiological roles of this key fibrinolytic protein and its proteolytic derivatives, plasmin and angiostatin, in development, hemostasis, and reproduction. Plg-/- mice complete embryonic development, survive to adulthood, and are fertile. There is no evidence of fetal loss of Plg-/- mice based on the Mendelian pattern of transmission of the mutant Plg allele. Furthermore, embryonic development continues to term in the absence of endogenous, sibling-derived, or maternal Plg. However, Plg-/- mice are predisposed to severe thrombosis, and young animals developed multiple spontaneous thrombotic lesions in liver, stomach, colon, rectum, lung, pancreas, and other tissues. Fibrin deposition in the liver was a uniform finding in 5- to 21-week-old mice, and ulcerated lesions in the gastrointestinal tract and rectal tissue were common. A remarkable finding, considering the well-established linkage between plasmin and the proteolytic activation of plasminogen activators, was that the level of active urokinase-type plasminogen activator in urine was unaffected in Plg-/- mice. Therefore, Plg plays a pivotal role in fibrinolysis and hemostasis but is not essential for urokinase proenzyme activation, development, or growth to sexual maturity.
Bugge
T H
TH
Division of Basic Science Research, Children's Hospital Research Foundation, Cincinnati, Ohio 45229, USA.
Flick
M J
MJ
Daugherty
C C
CC
Degen
J L
JL
D043168:Angiostatins; D000818:Animals; D001483:Base Sequence; D005314:Embryonic and Fetal Development / Q000502:physiology*; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis / Q000502:physiology; D006487:Hemostasis / Q000502:physiology; D008099:Liver / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments / Q000502:physiology; D010958:Plasminogen / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D012098:Reproduction / Q000502:physiology*; D013927:Thrombosis / Q000209:etiology*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D012333:RNA, Messenger; D043168:Angiostatins; D005337:Fibrin; D010958:Plasminogen; D014568:Urokinase-Type Plasminogen Activator