{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T05:55:54Z","timestamp":1791093354427,"version":"4.1.0"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[1995,11]]},"abstract":"\n Background<\/jats:italic>\n Circumstantial evidence suggests that the plasminogen\/plasmin system plays a role in many biological processes, including hemostasis, cell migration, and development.\n <\/jats:p>\n \n Methods and Results<\/jats:italic>\n The in vivo function of the plasminogen\/plasmin system was studied by generation of plasminogen-deficient (\n Plg<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n ) mice. Inactivation of the murine plasminogen gene (\n Plg<\/jats:italic>\n ) was achieved by replacing, via homologous recombination in embryonic stem cells, genomic sequences encoding the exons containing the catalytic site amino acids His\n 605<\/jats:sup>\n and Asp\n 648<\/jats:sup>\n with a neomycin phosphotransferase expression cassette. Germline transmission of the mutated allele, as determined by Southern blot hybridization and polymerase chain reaction, was obtained via blastocyst injection. Mendelian inheritance of the inactivated plasminogen allele was observed, and homozygous-deficient mice (\n Plg<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n ) displayed normal viability but retarded growth up to at least 12 weeks of age. At 8 weeks of age, body weight was 21.8\u00b11.2 g (n=10) for wild-type (\n Plg<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n ) mice, 21.0\u00b11.1 g (n=16) for heterozygous-deficient (\n Plg<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n ) mice, and 17.4\u00b11.3 g (n=12) for\n Plg<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice;\n P<\/jats:italic>\n <.05 versus\n Plg<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n or\n Plg<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n . None of 36\n Plg<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n or 65\n Plg<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice but 7 of 37\n Plg<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice (19%) developed rectal prolapse at 7.4\u00b10.6 weeks of age (\n P<\/jats:italic>\n =.03 versus\n Plg<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n and\n P<\/jats:italic>\n =.003 versus\n Plg<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n ); 4 of 37\n Plg<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice (11%) became runted and apathic at 5.3\u00b10.3 weeks of age (\n P<\/jats:italic>\n =.041 versus\n Plg<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n ); and 6 of 37\n Plg<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice (16%) died prematurely at 8.8\u00b11.7 weeks of age (\n P<\/jats:italic>\n =.057 versus\n Plg<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n and\n P<\/jats:italic>\n =.029 versus\n Plg<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n ). Although male and female\n Plg<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice were able to sire offspring, the fertility of\n Plg<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n female mice was reduced, possibly owing to their impaired health. Levels of plasminogen-related antigen in plasma, measured by ELISA, were 84\u00b18 \u03bcg\/mL (n=4) in\n Plg<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n , 35\u00b12 \u03bcg\/mL (n=3) in\n Plg<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n , and 0.076\u00b10.032 \u03bcg\/mL (n=6) in\n Plg<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice (\n P<\/jats:italic>\n <.001 versus\n Plg<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n and\n Plg<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n ). Plasmin activity generated by urokinase activation was unmeasurable in\n Plg<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice (<5% of\n Plg<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n mice). Plasminogen-specific immunoreactivity was observed in hepatocytes from\n Plg<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n mice but not from\n Plg<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice (<10% of\n Plg<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n mice). Neither native nor variant plasminogen mRNA nor translation products could be identified by Northern or Western blot of liver extracts from\n Plg<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice. Spontaneous lysis within 24 hours of a\n 125<\/jats:sup>\n I-fibrin\u2013labeled pulmonary plasma clot was 85\u00b15% (n=5) in\n Plg<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n mice, 62\u00b17% (n=3) in\n Plg<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice, and \u22122\u00b11% (n=3) in\n Plg<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice (\n P<\/jats:italic>\n <.001 versus\n Plg<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n and\n Plg<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n ). Delayed clot lysis within 72 hours was 33\u00b11% (n=3) in\n tPA<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice and 26\u00b12% (n=3) in\n Plg<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice (\n P<\/jats:italic>\n =.054). Histological examination of several organs revealed fibrin deposition in the liver; lung; and in the stomach, associated with gastric ulcers, in 6- to 12-week-old\n Plg<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n mice but not in\n Plg<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n or\n Plg<\/jats:italic>\n \n +\/\u2212<\/jats:italic>\n <\/jats:sup>\n littermates.\n <\/jats:p>\n \n Conclusions<\/jats:italic>\n Plasminogen-deficient mice survive embryonic development but develop spontaneous fibrin deposition due to impaired thrombolysis and suffer retarded growth and reduced fertility and survival. The\n Plg<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n phenotype is reminiscent of the combined\n tPA<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n :\n uPA<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n phenotype, which suggests that there is no significant additional pathway for physiological plasminogen activation in mice.\n <\/jats:p>","DOI":"10.1161\/01.cir.92.9.2585","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:34:42Z","timestamp":1339461282000},"page":"2585-2593","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":313,"title":["Effects of Disruption of The Plasminogen Gene on Thrombosis, Growth, and Health in Mice"],"prefix":"10.1161","volume":"92","author":[{"given":"Victoria A.","family":"Ploplis","sequence":"first","affiliation":[{"name":"From the Center for Transgene Technology and Gene Therapy (V.A.P., P.C., S.V., I.V.V., L.M., D.C.), Vlaams Interuniversitair Instituut voor Biotechnologie, KU Leuven, Belgium, and the Joseph J. Jacobs Center for Thrombosis and Vascular Biology and the Department of Molecular Cardiology (V.A.P., S.V., E.F.P.), Cleveland Clinic Foundation, Cleveland, Ohio."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Carmeliet","sequence":"additional","affiliation":[{"name":"From the Center for Transgene Technology and Gene Therapy (V.A.P., P.C., S.V., I.V.V., L.M., D.C.), Vlaams Interuniversitair Instituut voor Biotechnologie, KU Leuven, Belgium, and the Joseph J. Jacobs Center for Thrombosis and Vascular Biology and the Department of Molecular Cardiology (V.A.P., S.V., E.F.P.), Cleveland Clinic Foundation, Cleveland, Ohio."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahrzad","family":"Vazirzadeh","sequence":"additional","affiliation":[{"name":"From the Center for Transgene Technology and Gene Therapy (V.A.P., P.C., S.V., I.V.V., L.M., D.C.), Vlaams Interuniversitair Instituut voor Biotechnologie, KU Leuven, Belgium, and the Joseph J. Jacobs Center for Thrombosis and Vascular Biology and the Department of Molecular Cardiology (V.A.P., S.V., E.F.P.), Cleveland Clinic Foundation, Cleveland, Ohio."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilse","family":"Van Vlaenderen","sequence":"additional","affiliation":[{"name":"From the Center for Transgene Technology and Gene Therapy (V.A.P., P.C., S.V., I.V.V., L.M., D.C.), Vlaams Interuniversitair Instituut voor Biotechnologie, KU Leuven, Belgium, and the Joseph J. Jacobs Center for Thrombosis and Vascular Biology and the Department of Molecular Cardiology (V.A.P., S.V., E.F.P.), Cleveland Clinic Foundation, Cleveland, Ohio."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lieve","family":"Moons","sequence":"additional","affiliation":[{"name":"From the Center for Transgene Technology and Gene Therapy (V.A.P., P.C., S.V., I.V.V., L.M., D.C.), Vlaams Interuniversitair Instituut voor Biotechnologie, KU Leuven, Belgium, and the Joseph J. Jacobs Center for Thrombosis and Vascular Biology and the Department of Molecular Cardiology (V.A.P., S.V., E.F.P.), Cleveland Clinic Foundation, Cleveland, Ohio."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward F.","family":"Plow","sequence":"additional","affiliation":[{"name":"From the Center for Transgene Technology and Gene Therapy (V.A.P., P.C., S.V., I.V.V., L.M., D.C.), Vlaams Interuniversitair Instituut voor Biotechnologie, KU Leuven, Belgium, and the Joseph J. 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Lancet. 1989;1057-1062.","DOI":"10.1016\/S0140-6736(89)91078-7"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/01.CIR.92.9.2585","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T16:03:35Z","timestamp":1715529815000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/01.CIR.92.9.2585"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1995,11]]},"references-count":29,"journal-issue":{"issue":"9","published-print":{"date-parts":[[1995,11]]}},"alternative-id":["10.1161\/01.CIR.92.9.2585"],"URL":"https:\/\/doi.org\/10.1161\/01.cir.92.9.2585","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[1995,11]]},"assertion":[{"value":"1995-03-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"1995-06-08","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"1995-11-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}