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Since the binding of urokinase to urokinase receptors activates signaling responses and may stimulate mitogenesis, we assessed the effect of HKa binding on endothelial cell proliferation. Unexpectedly, HKa inhibited proliferation in response to several growth factors, with 50% inhibition caused by ~10 nM HKa. This activity was Zn\n                    <jats:sup>2+<\/jats:sup>\n                    dependent and not shared by either single\u2010chain high molecular weight kininogen (HK) or low molecular weight kininogen. HKa selectively inhibited the proliferation of human umbilical vein and dermal microvascular endothelial cells, but did not affect that of umbilical vein or human aortic smooth muscle cells, trophoblasts, fibroblasts, or carcinoma cells. Inhibition of endothelial proliferation by HKa was associated with endothelial cell apoptosis and unaffected by antibodies that block the binding of HK or HKa to any of their known endothelial receptors. Recombinant HK domain 5 displayed activity similar to that of HKa.\n                    <jats:italic>In vivo, HKa<\/jats:italic>\n                    inhibited neovascularization of subcutaneously implanted Matrigel plugs, as well as rat corneal angiogenesis. These results demonstrate that HKa is a novel inhibitor of angiogenesis, whose activity is dependent on the unique conformation of the two\u2010chain molecule.\u2014Zhang, J.\u2010C., Claffey, K., Sakthivel, R., Darzynkiewicz, Z., Shaw, D. E., Leal, J., Wang, Y.\u2010C., Lu, F. M., McCrae, K. R. Two\u2010chain high molecular weight kininogen induces endothelial cell apoptosis and inhibits angiogenesis: partial activity within domain 5.\n                    <jats:italic>The FASEB J.<\/jats:italic>\n                    14, 2589\u20132600 (2000)\n                  <\/jats:p>","DOI":"10.1096\/fj.99-1025com","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T19:03:24Z","timestamp":1027710204000},"page":"2589-2600","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":99,"title":["Two\u2010chain high molecular weight kininogen induces endothelial cell apoptosis and inhibits angiogenesis: partial activity within domain 5"],"prefix":"10.1096","volume":"14","author":[{"given":"Jing\u2010Chuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Hematology-Oncology Division Case Western Reserve University School of Medicine Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Claffey","sequence":"additional","affiliation":[{"name":"Department of Physiology, Center for Vascular Biology University of Connecticut School of Medicine Farmington Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramasamy","family":"Sakthivel","sequence":"additional","affiliation":[{"name":"Hematology-Oncology Division Case Western Reserve University School of Medicine Cleveland Ohio USA"},{"name":"Department of Medicine Case Western Reserve University School of Medicine Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zbigniev","family":"Darzynkiewicz","sequence":"additional","affiliation":[{"name":"New York Medical College Valhalla New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Elliot","family":"Shaw","sequence":"additional","affiliation":[{"name":"D.E. Shaw &amp; Co., Inc., New York New York and Attenuon L.L.C San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Leal","sequence":"additional","affiliation":[{"name":"Department of Chemotherapeutics, Pharmaceutical Product Division Abbott Laboratories Abbott Park Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010chun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemotherapeutics, Pharmaceutical Product Division Abbott Laboratories Abbott Park Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng\u2010min","family":"Lu","sequence":"additional","affiliation":[{"name":"Center for Neurovirology and Neurooncology Allegheny University of the Health Sciences Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith R.","family":"McCrae","sequence":"additional","affiliation":[{"name":"Hematology-Oncology Division Case Western Reserve University School of Medicine Cleveland Ohio USA"},{"name":"Department of Medicine Case Western Reserve University School of Medicine Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2000,12]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0195-27"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80108-7"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)49853-0"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.5.2002"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199101033240101"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9378(98)80018-5"},{"key":"e_1_2_5_8_1","first-page":"401","article-title":"Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma","volume":"143","author":"Weidner N.","year":"1993","journal-title":"Am. 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