{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T20:40:07Z","timestamp":1770496807620,"version":"3.49.0"},"reference-count":102,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2004,2,19]],"date-time":"2004-02-19T00:00:00Z","timestamp":1077148800000},"content-version":"vor","delay-in-days":3489,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Cellular Biochemistry"],"published-print":{"date-parts":[[1994,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A tightly controlled increase in extracellular proteolysis, restricted both in time and space, is an important component of the angiogenic process, while anti\u2010proteolysis is effective in inhibiting angiogenesis. By focussing on the plasminogen activator (PA)\u2010plasmin system, the objective of the present studies was to assess whether previously described inhibitors of angiogenesis modify bovine microvascular endothelial cell proteolytic properties. We demonstrate that although synthetic angiostatic steroids (U\u201024067 and U\u201042129), heparin, suramin, interferon alpha\u20102a, and retinoic acid are all inhibitors of in vitro angiogenesis, each of these agents has distinct effects on the plasminogen\u2010dependent proteolytic system. Specifically, angiostatic steroids and interferon alpha\u20102a reduce urokinase\u2010type PA (u\u2010PA) and PA inhibitor\u20101 activity, while heparin and retinoic acid increase u\u2010PA activity. Suramin reduces cell\u2010associated u\u2010PA activity and greatly increases PAI\u20101 production at doses which induce monolayer disruption. These findings demonstrate that a spectrum of alterations in extracellular proteolysis is associated with anti\u2010angiogenesis, and that anti\u2010angiogenesis and anti\u2010proteolysis are not necessarily correlated. A reduction in extracellular proteolysis would be expected to reduce invasion, whereas an increase in proteolysis might modulate the activity of inhibitory cytokines, which in turn could reduce endothelial cell proliferation and migration and inhibit angiogenesis. The spectrum of effects on different elements of the PA system observed in response to the agents assessed suggests that the role of modulations in extracellular proteolytic activity in anti\u2010angiogenesis is likely to be varied and complex. \u00a9 1994 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcb.240550403","type":"journal-article","created":{"date-parts":[[2005,5,28]],"date-time":"2005-05-28T21:41:53Z","timestamp":1117316513000},"page":"419-434","source":"Crossref","is-referenced-by-count":64,"title":["Modulation of bovine microvascular endothelial cell proteolytic properties by inhibitors of angiogenesis"],"prefix":"10.1002","volume":"55","author":[{"given":"M. S.","family":"Pepper","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.\u2010D.","family":"Vassalli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L.","family":"Orci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R.","family":"Montesano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. W.","family":"Wilks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L.","family":"Schweigerer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2004,2,19]]},"reference":[{"key":"e_1_2_1_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00362a007"},{"key":"e_1_2_1_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910440519"},{"key":"e_1_2_1_4_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.152.4.931"},{"key":"e_1_2_1_5_1","doi-asserted-by":"crossref","first-page":"5985","DOI":"10.1016\/S0021-9258(18)53416-5","article-title":"Binding of urokinase\u2010type plasminogen activator to its cell surface receptor is inhibited by low doses of suramin","volume":"268","author":"Behrendt N","year":"1993","journal-title":"J Biol Chem"},{"key":"e_1_2_1_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041550315"},{"key":"e_1_2_1_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0026-2862(91)90007-X"},{"key":"e_1_2_1_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.6154315"},{"key":"e_1_2_1_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/0309-1651(88)90028-8"},{"key":"e_1_2_1_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041270221"},{"key":"e_1_2_1_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.79.18.5597"},{"key":"e_1_2_1_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041320120"},{"key":"e_1_2_1_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.240520305"},{"key":"e_1_2_1_14_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116486"},{"key":"e_1_2_1_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2416056"},{"key":"e_1_2_1_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/81.7.497"},{"key":"e_1_2_1_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0277-5379(90)90018-O"},{"key":"e_1_2_1_18_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199205283262203"},{"key":"e_1_2_1_19_1","doi-asserted-by":"crossref","first-page":"11223","DOI":"10.1016\/S0021-9258(17)39169-X","article-title":"Isolation and characterization of the human tissue\u2010type plasminogen activator structural gene including its 5\u2032 flanking region","volume":"260","author":"Fisher R","year":"1985","journal-title":"J Biol Chem"},{"key":"e_1_2_1_20_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.118.4.901"},{"key":"e_1_2_1_21_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.3.10.1057"},{"key":"e_1_2_1_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2432664"},{"key":"e_1_2_1_23_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.6192498"},{"key":"e_1_2_1_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2467380"},{"key":"e_1_2_1_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.7.2690"},{"key":"e_1_2_1_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/368237a0"},{"key":"e_1_2_1_27_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.98.3.1033"},{"key":"e_1_2_1_28_1","first-page":"5073","article-title":"Inhibition of angiogenesis by suramin","volume":"52","author":"Gagliardi A","year":"1992","journal-title":"Cancer Res"},{"key":"e_1_2_1_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041270116"},{"key":"e_1_2_1_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041280317"},{"key":"e_1_2_1_31_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.78.2.1176"},{"key":"e_1_2_1_32_1","first-page":"5164","article-title":"Evaluation of the effect of suramin on neural cell growth and N\u2010CAM expression","volume":"30","author":"Guo X\u2010J","year":"1990","journal-title":"Cancer Res"},{"key":"e_1_2_1_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4827(85)90087-4"},{"key":"e_1_2_1_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(85)90399-7"},{"key":"e_1_2_1_35_1","first-page":"44","article-title":"Inhibition of angiogenesis through modulation of collagen metabolism","volume":"59","author":"Ingber D","year":"1988","journal-title":"Lab Invest"},{"key":"e_1_2_1_36_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo-119-4-1768"},{"key":"e_1_2_1_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0773.1991.tb01284.x"},{"key":"e_1_2_1_38_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ph.53.030191.001245"},{"key":"e_1_2_1_39_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.9.2.147"},{"key":"e_1_2_1_40_1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.2220\/biomedres.7.155","article-title":"Synergism of retinoids and L\u2010ascorbic acid in producing plasminogen activator in endothelial cells","volume":"7","author":"Kojima S","year":"1986","journal-title":"Biomed Res"},{"key":"e_1_2_1_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041550213"},{"key":"e_1_2_1_42_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI113635"},{"key":"e_1_2_1_43_1","first-page":"565","article-title":"Stimulation of tissue\u2010type plasminogen activator synthesis by retinoids in cultured human endothelial cells and rat tissues in vivo","volume":"65","author":"Kooistra T","year":"1991","journal-title":"Thromb Hem"},{"key":"e_1_2_1_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(93)90325-W"},{"key":"e_1_2_1_45_1","first-page":"106","article-title":"Suramin: Prototype of a new generation of antitumor compounds","volume":"2","author":"La Rocca RV","year":"1990","journal-title":"Cancer Cells"},{"key":"e_1_2_1_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041460121"},{"key":"e_1_2_1_47_1","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1182\/blood.V80.4.981.bloodjournal804981","article-title":"Stimulation of tissue plasminogen activator production by retinoic acid: synergistic effect on protein kinase C\u2010mediated activation","volume":"80","author":"Medh RD","year":"1992","journal-title":"Blood"},{"key":"e_1_2_1_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041090209"},{"key":"e_1_2_1_49_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00152a044"},{"key":"e_1_2_1_50_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.113.5.1193"},{"key":"e_1_2_1_51_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.108.2.671"},{"key":"e_1_2_1_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(85)90104-7"},{"key":"e_1_2_1_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90009-4"},{"key":"e_1_2_1_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041320313"},{"key":"e_1_2_1_55_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.83.19.7297"},{"key":"e_1_2_1_56_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.83.7.2091"},{"key":"e_1_2_1_57_1","first-page":"67","article-title":"Membrane and matrix localization of proteases: A common theme in tumor invasion and angiogenesis","volume":"948","author":"Moscatelli D","year":"1988","journal-title":"Biochim Biophys Acta"},{"key":"e_1_2_1_58_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1694043"},{"key":"e_1_2_1_59_1","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1182\/blood.V79.3.678.678","article-title":"Tumor necrosis factor induction of endothelial cell urokinase\u2010type plasminogen activator mediated proteolysis of extracellular matrix and its antagonism by \u03b3\u2010interferon","volume":"79","author":"Niedbala MJ","year":"1992","journal-title":"Blood"},{"key":"e_1_2_1_60_1","first-page":"147","article-title":"Heparin enhances angiogenesis by a systemic mode of action","volume":"73","author":"Norrby K","year":"1992","journal-title":"Int J Exp Pathol"},{"key":"e_1_2_1_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3835(89)90054-2"},{"key":"e_1_2_1_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/0277-5379(90)90186-W"},{"key":"e_1_2_1_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(89)90694-6"},{"key":"e_1_2_1_64_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.111.2.743"},{"key":"e_1_2_1_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/0922-3371(90)90046-Y"},{"key":"e_1_2_1_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(05)80231-1"},{"key":"e_1_2_1_67_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.122.3.673"},{"key":"e_1_2_1_68_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.105.6.2535"},{"key":"e_1_2_1_69_1","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1993.1043"},{"key":"e_1_2_1_70_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1992.272"},{"key":"e_1_2_1_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(17)38291-5"},{"key":"e_1_2_1_72_1","doi-asserted-by":"publisher","DOI":"10.1159\/000146454"},{"key":"e_1_2_1_73_1","doi-asserted-by":"publisher","DOI":"10.1016\/0309-1651(86)90039-1"},{"key":"e_1_2_1_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(88)80732-0"},{"key":"e_1_2_1_75_1","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12514496"},{"key":"e_1_2_1_76_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.105.2.957"},{"key":"e_1_2_1_77_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.107.2.743"},{"key":"e_1_2_1_78_1","first-page":"9","article-title":"Mechanism of the synergistic effect of heparin and cortisone against angiogenesis and tumor growth","volume":"2","author":"Sakamoto N","year":"1988","journal-title":"Cancer J"},{"key":"e_1_2_1_79_1","first-page":"55","article-title":"Heparin plus cortisone acetate inhibit tumor growth by blocking endothelial cell proliferation","volume":"1","author":"Sakamoto N","year":"1986","journal-title":"Cancer J"},{"key":"e_1_2_1_80_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.107.3.1199"},{"key":"e_1_2_1_81_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.18.6138"},{"key":"e_1_2_1_82_1","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1093\/jnci\/57.4.769","article-title":"Vascularization induced in the cheek pouch of the syrian hamster by tumor and nontumor substances","volume":"57","author":"Shubik P","year":"1976","journal-title":"J Natl Cancer Inst"},{"key":"e_1_2_1_83_1","first-page":"5155","article-title":"Inhibition of angiogenesis by interferons: Effects on tumor\u2010 and lymphocyte\u2010induced vascular responses","volume":"47","author":"Sidkey YA","year":"1987","journal-title":"Cancer Res"},{"key":"e_1_2_1_84_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041380129"},{"key":"e_1_2_1_85_1","first-page":"2239","article-title":"Suramin: A novel antineoplastic agent with multiple potential mechanisms of action","volume":"53","author":"Stein CA","year":"1993","journal-title":"Cancer Res"},{"key":"e_1_2_1_86_1","doi-asserted-by":"publisher","DOI":"10.1159\/000247516"},{"key":"e_1_2_1_87_1","doi-asserted-by":"publisher","DOI":"10.1038\/297307a0"},{"key":"e_1_2_1_88_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1991.tb16323.x"},{"key":"e_1_2_1_89_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.6635659"},{"key":"e_1_2_1_90_1","first-page":"3000","article-title":"Heparin\u2010steroid conjugates: New angiogenesis inhibitors with antitumor activity in mice","volume":"53","author":"Thorpe PE","year":"1993","journal-title":"Cancer Res"},{"key":"e_1_2_1_91_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(88)81104-5"},{"key":"e_1_2_1_92_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(87)80039-X"},{"key":"e_1_2_1_93_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.159.6.1653"},{"key":"e_1_2_1_94_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115405"},{"key":"e_1_2_1_95_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198905043201807"},{"key":"e_1_2_1_96_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(05)81844-X"},{"key":"e_1_2_1_97_1","first-page":"159","volume-title":"Steroid Hormones and Uterine Bleeding","author":"Wilks JW","year":"1992"},{"key":"e_1_2_1_98_1","doi-asserted-by":"publisher","DOI":"10.1080\/09553009114551581"},{"key":"e_1_2_1_99_1","first-page":"911","article-title":"Hyperthermia stimulates plasminogen activator inhibitor type 1 expression in human umbilical vein endothelial cells in vitro","volume":"139","author":"Wojta J","year":"1991","journal-title":"Am J Physiol"},{"key":"e_1_2_1_100_1","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1182\/blood.V71.6.1703.1703","article-title":"Reduction in pO2 decreases the fibrinolytic potential of cultured bovine endothelial cells derived from pulmonary arteries and lung microvasculature","volume":"71","author":"Wojta J","year":"1988","journal-title":"Blood"},{"key":"e_1_2_1_101_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(92)92407-O"},{"key":"e_1_2_1_102_1","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1182\/blood.V69.5.1348.1348","article-title":"Immunoradiometric quantitation of tissue plasminogen activator\u2010related antigen in human plasma: Crypticity phenomenon and relationship to plasma fibrinolysis","volume":"69","author":"Wun T\u2010C","year":"1987","journal-title":"Blood"},{"key":"e_1_2_1_103_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.93.3_Supplement.159S"}],"container-title":["Journal of Cellular Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjcb.240550403","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcb.240550403","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T04:41:30Z","timestamp":1698208890000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcb.240550403"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1994,8]]},"references-count":102,"journal-issue":{"issue":"4","published-print":{"date-parts":[[1994,8]]}},"alternative-id":["10.1002\/jcb.240550403"],"URL":"https:\/\/doi.org\/10.1002\/jcb.240550403","archive":["Portico"],"relation":{},"ISSN":["0730-2312","1097-4644"],"issn-type":[{"value":"0730-2312","type":"print"},{"value":"1097-4644","type":"electronic"}],"subject":[],"published":{"date-parts":[[1994,8]]}}}