Bugge T H, Flick M J, Daugherty C C, Degen J L
Division of Basic Science Research, Children's Hospital Research Foundation, Cincinnati, Ohio 45229, USA.
Genes Dev. 1995 Apr 1;9(7):794-807. doi: 10.1101/gad.9.7.794.
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.
为了确定这种关键的纤维蛋白溶解蛋白及其蛋白水解衍生物纤溶酶和血管抑素在发育、止血和生殖中的生理作用，构建了纤溶酶原（Plg）缺陷小鼠。Plg-/-小鼠完成胚胎发育，存活至成年且具有生育能力。基于突变型Plg等位基因的孟德尔遗传模式，没有证据表明Plg-/-小鼠存在胎儿丢失的情况。此外，在没有内源性、同胞来源或母体Plg的情况下，胚胎发育仍可持续至足月。然而，Plg-/-小鼠易发生严重血栓形成，幼龄动物在肝脏、胃、结肠、直肠、肺、胰腺和其他组织中出现多个自发性血栓性病变。在5至21周龄的小鼠中，肝脏中的纤维蛋白沉积是一个普遍现象，胃肠道和直肠组织中的溃疡病变也很常见。考虑到纤溶酶与纤溶酶原激活剂的蛋白水解激活之间已确立的联系，一个显著的发现是，Plg-/-小鼠尿液中活性尿激酶型纤溶酶原激活剂的水平未受影响。因此，Plg在纤维蛋白溶解和止血中起关键作用，但对于尿激酶原的激活、发育或性成熟生长并非必不可少。
