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Blood, 15 January 2008, Vol. 111, No. 2, pp. 613-623. Prepublished online as a Blood First Edition Paper on September 21, 2007; DOI 10.1182/blood-2007-06-098392. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-06-098392v1 111/2/613    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Isenberg, J. S. Articles by Roberts, D. D. Search for Related Content PubMed PubMed Citation Articles by Isenberg, J. S. Articles by Roberts, D. D. Related Collections Hemostasis, Thrombosis, and Vascular Biology Cell Adhesion and Motility Signal Transduction Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Thrombospondin-1 stimulates platelet aggregation by blocking the antithrombotic activity of nitric oxide/cGMP signaling Jeff S. Isenberg1, Martin J. Romeo1, Christine Yu1, Christine K. Yu1, Khauh Nghiem2, Jude Monsale2, Margaret E. Rick2, David A. Wink3, William A. Frazier4, and David D. Roberts1 1 Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD; 2 Hematology Service, Clinical Center, NIH, Bethesda, MD; 3 Radiation Biology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD; and 4 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO Platelet -granules constitute the major rapidly releasable reservoir of thrombospondin-1 in higher animals. Although some fragments and peptides derived from thrombospondin-1 stimulate or inhibit platelet aggregation, its physiologic function in platelets has remained elusive. We now show that endogenous thrombospondin-1 is necessary for platelet aggregation in vitro in the presence of physiologic levels of nitric oxide (NO). Exogenous NO or elevation of cGMP delays thrombin-induced platelet aggregation under high shear and static conditions, and exogenous thrombospondin-1 reverses this delay. Thrombospondin-1–null murine platelets fail to aggregate in response to thrombin in the presence of exogenous NO or 8Br-cGMP. At physiologic concentrations of the NO synthase substrate arginine, thrombospondin-1–null platelets have elevated basal cGMP. Ligation of CD36 or CD47 is sufficient to block NO-induced cGMP accumulation and mimic the effect of thrombospondin-1 on aggregation. Exogenous thrombospondin-1 also reverses the suppression by NO of IIb/β3 integrin–mediated platelet adhesion on immobilized fibrinogen, mediated in part by increased GTP loading of Rap1. Thrombospondin-1 also inhibits cGMP-mediated activation of cGMP-dependent protein kinase and thereby prevents phosphorylation of VASP. Thus, release of thrombospondin-1 from -granules during activation provides positive feedback to promote efficient platelet aggregation and adhesion by overcoming the antithrombotic activity of physiologic NO. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Secreted thrombospondin-1 controls platelet sensitivity to NO Deane F. Mosher, Lisa M. Maurer, and C. Britt Carlson Blood 2008 111: 473-474. [Full Text] [PDF] This article has been cited by other articles: J. B. Maxhimer, D. R. Soto-Pantoja, L. A. Ridnour, H. B. Shih, W. G. DeGraff, M. Tsokos, D. A. Wink, J. S. Isenberg, and D. D. Roberts Radioprotection in Normal Tissue and Delayed Tumor Growth by Blockade of CD47 Signaling Science Translational Medicine, October 21, 2009; 1(3): 3ra7 - 3ra7. [Abstract] [Full Text] [PDF] O. Uluckan, S. N. Becker, H. Deng, W. Zou, J. L. Prior, D. Piwnica-Worms, W. A. Frazier, and K. N. Weilbaecher CD47 Regulates Bone Mass and Tumor Metastasis to Bone Cancer Res., April 1, 2009; 69(7): 3196 - 3204. [Abstract] [Full Text] [PDF] A. Reheman, H. Yang, G. Zhu, W. Jin, F. He, C. M. Spring, X. Bai, P. L. Gross, J. Freedman, and H. Ni Plasma fibronectin depletion enhances platelet aggregation and thrombus formation in mice lacking fibrinogen and von Willebrand factor Blood, February 19, 2009; 113(8): 1809 - 1817. [Abstract] [Full Text] [PDF] M. M. Krady, J. Zeng, J. Yu, S. MacLauchlan, E. A. Skokos, W. Tian, P. Bornstein, W. C. Sessa, and T. R. Kyriakides Thrombospondin-2 Modulates Extracellular Matrix Remodeling during Physiological Angiogenesis Am. J. Pathol., September 1, 2008; 173(3): 879 - 891. [Abstract] [Full Text] [PDF] J. S. Isenberg, D. D. Roberts, and W. A. Frazier CD47: A New Target in Cardiovascular Therapy Arterioscler Thromb Vasc Biol, April 1, 2008; 28(4): 615 - 621. [Abstract] [Full Text] [PDF]

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