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Blood, 15 February 2004, Vol. 103, No. 4, pp. 1185-1191. Prepublished online as a Blood First Edition Paper on October 16, 2003; DOI 10.1182/blood-2003-08-2920. This Article Full Text (PDF) All Versions of this Article: 2003-08-2920v1 103/4/1185    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zhang, W. Articles by Olson, S. T Search for Related Content PubMed PubMed Citation Articles by Zhang, W. Articles by Olson, S. T Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Submitted August 29, 2003 Accepted October 2, 2003 Anti-angiogenic antithrombin downregulates the expression of the pro-angiogenic heparan sulfate proteoglycan, perlecan, in endothelial cells Weiqing Zhang, Yung-Jen Chuang, Richard Swanson, Juan Li, Kyunga Seo, Lawrence Leung, Lester F Lau, and Steven T Olson* Center for Molecular Biology of Oral Diseases, University of Illinois at Chicago, Chicago, IL, USA Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA Department of Medicine, Stanford University Medical Center, Stanford, CA, USA * Corresponding author; email: stolson{at}uic.edu. Antithrombin, a key serpin family regulator of blood coagulation proteases, is transformed into a potent anti-angiogenic factor by limited proteolysis or mild heating. Here, we show by cDNA microarray, semiquantitative RT-PCR, Northern blotting and immunoblotting analyses that the expression of the pro-angiogenic heparan sulfate proteoglycan (HSPG), perlecan, but not other HSPGs, is dramatically downregulated in human umbilical vein endothelial cells (HUVECs) treated with anti-angiogenic cleaved and latent forms of antithrombin, but not with the native form. Downregulation of perlecan expression by cleaved and latent antithrombins was observed in both basic fibroblast growth factor (bFGF)-stimulated and unstimulated cells, whereas the anti-angiogenic antithrombins inhibited the proliferation of only bFGF-stimulated HUVECs by arresting cells at the G1 cell cycle phase. The importance of perlecan expression levels in mediating the anti-proliferative effect of the anti-angiogenic antithrombins was suggested by the finding that transforming growth factor-1, a potent stimulator of perlecan expression in endothelial cells, blocked the downregulation of perlecan expression and anti-proliferative activity of cleaved antithrombin on endothelial cells. The previously established key role of perlecan in mediating bFGF stimulation of endothelial cell proliferation and angiogenesis suggests that a primary mechanism by which anti-angiogenic antithrombins exert their effects is through the downregulation of perlecan expression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: And a final message from antithrombin Robin Carrell Blood 2004 103: 1179. [Full Text] [PDF] This article has been cited by other articles: N. Parmar, L. R. Berry, M. Post, and A. K. C. Chan Effect of covalent antithrombin-heparin complex on developmental mechanisms in the lung Am J Physiol Lung Cell Mol Physiol, March 1, 2009; 296(3): L394 - L403. [Abstract] [Full Text] [PDF] G. J. del Zoppo, R. Milner, T. Mabuchi, S. Hung, X. Wang, G. I. Berg, and J. A. Koziol Microglial Activation and Matrix Protease Generation During Focal Cerebral Ischemia Stroke, February 1, 2007; 38(2): 646 - 651. [Abstract] [Full Text] [PDF] W. Zhang, R. Swanson, Y. Xiong, B. Richard, and S. T. Olson Antiangiogenic Antithrombin Blocks the Heparan Sulfate-dependent Binding of Proangiogenic Growth Factors to Their Endothelial Cell Receptors: EVIDENCE FOR DIFFERENTIAL BINDING OF ANTIANGIOGENIC AND ANTICOAGULANT FORMS OF ANTITHROMBIN TO PROANGIOGENIC HEPARAN SULFATE DOMAINS J. Biol. Chem., December 8, 2006; 281(49): 37302 - 37310. [Abstract] [Full Text] [PDF] W. Zhang, Y.-J. Chuang, T. Jin, R. Swanson, Y. Xiong, L. Leung, and S. T. Olson Antiangiogenic antithrombin induces global changes in the gene expression profile of endothelial cells. Cancer Res., May 15, 2006; 66(10): 5047 - 5055. [Abstract] [Full Text] [PDF] W. Zhang, R. Swanson, G. Izaguirre, Y. Xiong, L. F. Lau, and S. T. Olson The heparin-binding site of antithrombin is crucial for antiangiogenic activity Blood, September 1, 2005; 106(5): 1621 - 1628. [Abstract] [Full Text] [PDF] D. W. J. van der Schaft, R. E. B. Seftor, E. A. Seftor, A. R. Hess, L. M. Gruman, D. A. Kirschmann, Y. Yokoyama, A. W. Griffioen, and M. J. C. Hendrix Effects of Angiogenesis Inhibitors on Vascular Network Formation by Human Endothelial and Melanoma Cells J Natl Cancer Inst, October 6, 2004; 96(19): 1473 - 1477. [Abstract] [Full Text] [PDF]

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