Role of thrombospondin-1 in control of von Willebrand factor multimer size in mice.
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 Tyr(842)-Met(843) 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 alpha-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.
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.
John E
JE
Pimanda
Tim
T
Ganderton
Akiko
A
Maekawa
Cindy L
CL
Yap
Jack
J
Lawler
Geoff
G
Kershaw
Colin N
CN
Chesterman
Philip J
PJ
Hogg
D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D004151:Dipeptides / Q000737:chemistry; D051379:Mice; D018345:Mice, Knockout; D019700:Thrombospondin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014841:von Willebrand Factor / Q000737:chemistry / Q000378:metabolism*
D004151:Dipeptides; D019700:Thrombospondin 1; D014841:von Willebrand Factor