Thrombospondin-1 in von Willebrand factor function.
Thrombospondin-1 (TSP1), expressed in many cells and tissues is abundantly present in platelet alpha-granules, from where it is released upon platelet activation. Murine Tsp1(-/-) platelet studies have revealed that TSP1 is redundant for platelet aggregation, but that it reinforces platelet aggregate stabilization, especially in a shear field. von Willebrand factor (VWF), synthesized by megakaryocytes and endothelial cells is stored both in platelet alpha-granules and in endothelial Weibel-Palade bodies as ultralarge multimers. When released from endothelial cells, these multimers are temporarily retained on the endothelium, to be cleaved by the plasma protease ADAMTS13 into smaller and hemostatically less reactive multimers, released in plasma. This protease shows partial sequence identity with the type 1 (TSR1) and type 2 (TSR2) repeats of TSP1 and contains 1 TSR1 and 6 TSR2 repeats. TSP1, locally released by platelets, competes with ADAMTS13 during VWF proteolysis and controls the degree of VWF multimer processing. In addition, TSP1 and VWF both interact with the platelet GPIb/V/IX membrane complex, primarily in flow. These interactions control the recruitment of platelets to (sub) endothelial VWF and TSP1, exposed to the circulation, as a consequence of vascular inflammation and endothelial injury. TSP1-VWF interactions do not strictly enhance platelet recruitment and secreted TSP1 even weakly competes with the dynamic platelet rolling and adhesion onto VWF. Hence, TSP1 and VWF show partially related hemostatic functions, the most important one being the TSP1 role in the ADAMTS13 operated VWF multimer processing, in pro-inflammatory and thrombogenic conditions.
INSERM U743, Centre de Recherche du Centre Hospitalier de l'Université de Montréal-Saint-Luc, Montréal QCH2X1P1, Canada.
Arnaud
A
Bonnefoy
Marc F
MF
Hoylaerts
D000818:Animals; D004730:Endothelium, Vascular / Q000737:chemistry / Q000502:physiology; D006487:Hemostasis / Q000502:physiology; D006801:Humans; D017434:Protein Structure, Tertiary / Q000502:physiology; D013312:Stress, Physiological; D013329:Structure-Activity Relationship; D019700:Thrombospondin 1 / Q000737:chemistry / Q000502:physiology*; D014841:von Willebrand Factor / Q000737:chemistry / Q000502:physiology*
D019700:Thrombospondin 1; D014841:von Willebrand Factor