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J. Biol. Chem., Vol. 279, Issue 20, 21439-21448, May 14, 2004

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Role of Thrombospondin-1 in Control of von Willebrand Factor Multimer Size in Mice^*

John E. Pimanda, Tim Ganderton, Akiko Maekawa, Cindy L. Yap, Jack Lawler¶, Geoff Kershaw||, Colin N. Chesterman, and Philip J. Hogg**

From the Centre for Vascular Research, University of New South Wales and the Department of Haematology, The Prince of Wales Hospital, Sydney, New South Wales 2052, Australia, Australian Centre for Blood Diseases, Department of Medicine, Monash University, Box Hill Hospital, Victoria 3128, Australia, the ^¶Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, and the ^||Department of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia

Plasma von Willebrand factor (VWF) is a multimeric glycoprotein from endothelial cells and platelets that mediates adhesion of platelets to sites of vascular injury. In the shear force of flowing blood, however, only the very large VWF multimers are effective in capturing platelets. The multimeric size of VWF can be controlled by proteolysis at the Tyr⁸⁴²-Met⁸⁴³ peptide bond by ADAMTS13 or cleavage of the disulfide bonds that hold VWF multimers together by thrombospondin-1 (TSP-1). The average multimer size of plasma VWF in TSP-1 null mice was significantly smaller than in wild type mice. In addition, the multimer size of VWF released from endothelium in vivo was reduced more rapidly in TSP-1 null mice than in wild type mice. TSP-1, like ADAMTS13, bound to the VWF A3 domain. TSP-1 in the wild type mice, therefore, may compete with ADAMTS13 for interaction with the A3 domain and slow the rate of VWF proteolysis. TSP-1 is stored in platelet -granules and is released upon platelet activation. Significantly, platelet VWF multimer size was reduced upon lysis or activation of wild type murine platelets but not TSP-1 null platelets. This difference had functional consequences in that there was an increase in collagen- and VWF-mediated aggregation of the TSP-1 null platelets under both static and shear conditions. These findings indicate that TSP-1 influences plasma and platelet VWF multimeric size differently and may be more relevant for control of the VWF released from platelets.

Received for publication, December 11, 2003 , and in revised form, February 11, 2004.

^* This work was supported by the National Health and Medical Research Council of Australia, the National Heart Foundation of Australia, the New South Wales Health Department, and HLBI, National Institutes of Health, Grant HL 68003. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Centre for Vascular Research, University of New South Wales, Sydney, New South Wales 2052, Australia. Tel.: 61-2-93851004; Fax: 61-2-93851389; E-mail: p.hogg{at}unsw.edu.au.

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