In vivo imaging analysis of the interaction between unusually large von Willebrand factor multimers and platelets on the surface of vascular wall
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- Rybaltowski, M., Suzuki, Y., Mogami, H. et al. Pflugers Arch - Eur J Physiol (2011) 461: 623. doi:10.1007/s00424-011-0958-x
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To elucidate how unusually large von Willebrand factor (UL-VWF) multimers facilitate thrombus formation, their behavior was analyzed together with that of platelets in living mice deficient in the gene encoding the protease that cleaves UL-VWF, a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13−/−). By crossing ADAMTS13−/− mice with green fluorescent protein-expressing transgenic mice (GFP mice), GFP-ADAMTS13−/− mice were obtained. The dynamics of GFP-expressing platelets were monitored employing intravital confocal fluorescent microscopy. Administration of a vasopressin derivative, DDAVP, a secretagogue of VWF increased the number of platelets adhered to vascular endothelial cells (VECs) on mesentery at sites recognized by an anti-VWF antibody. Some of these platelets were interconnected and aligned as beads on a string. They reached their maximum length at 5 min and were longer in GFP-ADAMTS13−/− mice than in GFP mice (5.3 ± 4.3, N = 6 vs 2.9 ± 2.1 μm, N = 4) (mean±SE). Focal injury of VECs by topical application of FeCl3 developed longer (25, 3–50 vs 10, 2–25 μm, P < 0.01) (mean, 10th–90th percentile) and more stable (1.3, 0.3–6.3 vs 0.3, 0.2–1.3 s, P < 0.01) connected platelets in GFP-ADAMTS13−/− mice than in GFP mice. This study revealed that ADAMTS13 cleaves platelet-bound UL-VWF multimers, both during their secretion from VECs and after their adherence to injured vascular walls in veins. UL-VWF multimers either being secreted from VECs or circulating in plasma of ADAMTS13−/− mice appeared to facilitate the accumulation of longer and more stable VWF strings with more associated platelets on injured vascular walls.