In vivo angiogenic activity of urokinase: role - Journal of Cell ...

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4220D. Ribatti and othersin the CAM, as suggested by the residual angiogenic activityexerted by PMSF-treated uPA. Relevant to this point, previousstudies have shown that purified uPA exerts an uPARdependentmitogenic activity on human fibroblasts that cannotbe mimicked by ATF alone, suggesting that both receptoroccupancy and catalytic activity may play a role in thebiological activity of uPA (De Petro et al., 1994).Transgenic mice lacking uPA and/or tissue-type PA(Carmeliet et al., 1994) or plasminogen (Bugge et al., 1995)develop normally, demonstrating that the proteolytic cascadetriggered by plasminogen activation is not a fundamentalcomponent for neovascularization during development. On theother hand, uPA/plasmin inhibitors affect angiogenesis in vitroand in vivo in different experimental models (Mignatti et al.,1989; Yasunaga et al., 1989; Avery et al., 1990; Bastaki et al.,1997). Also, the reduced rate of growth of murine experimentaltumors by anti-fibrinolytic drug-treatment may depend on areduced neovascularization (Astedt and Tropè, 1980; Corasantiet al., 1982; Teuscher and Pester, 1984). Finally, an alteredfibrinolytic status affects polyoma middle T-induced vasculartumor formation (Sabapathy et al., 1997). Our observationsindicate for the first time that uPA/plasmin-dependentdegradation of ECM, with the consequent mobilization ofstored angiogenesis factors, may represent one of themechanisms by which the fibrinolytic system modulatesangiogenesis in vivo.We thank A. Soffientini for the preparation of human ATF and G.De Petro for helpful discussion. This work was supported by grantsfrom Istituto Superiore di Sanità (AIDS Project), AssociazioneItaliana per la Ricerca sul Cancro, National Research Council (TargetProject on Biotechnology), by Ministero dell’Università e dellaRicerca Scientifica e Tecnologica (Cofinanziamento 1997‘Infiammazione: biologia e clinica’ and ‘60%’) to M.P.REFERENCESAstedt, B. and Tropé, C. (1980). Effect of tranexamic acid on progress ofexperimental tumours and on DNA synthesis. Experientia 36, 679-680.Avery, R. L., Connor, T. B. and Farazdaghi, M. (1990). Systemic amilorideinhibits experimentally induced neovascularization. Arch. Ophtalmol. 108,1474-1476.Bacharach, E., Itin, A. and Keshet, E. (1992). In vivo patterns of expressionof urokinase and its inhibitor PAI-1 suggest a concerted role in regulatingphysiological angiogenesis. Proc. Nat. Acad. Sci. USA 89, 10686-10690.Bashkin, P., Doctrow, S., Klagsbrun, M., Svahn, C. M., Folkman, J. andVlodavsky, I. (1989). 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