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* Blood Transfusion Unit,
Division for Experimental Oncology 2, The National Cancer Institute CRO-IRCCS, Aviano (PN) 33081 Italy;
Department for Cell and Molecular Biology, University of Lund, S-22184 Lund, Sweden;
MATI Centre of Excellence, University of Udine, Piazzale Kolbe, Udine, 35100 Italy; and
|| Department of Evolutionary and Functional Biology, University of Parma, 43100 Parma, Italy
1Correspondence: Department of Evolutionary and Functional Biology, The University of Parma, Viale delle Scienze 11/A, 43100 Parma, Italy. E-mail: rperris{at}cro.it; Blood Transfusion Unit, The National Cancer Institute CRO-IRCCS, Aviano 33081, Italy. Email ldemarco{at}cro.it
We have identified a novel von Willebrand factor/fibrinogen/selectin-independent, platelet adhesion-promoting function of vascular PG-M/versicans that may be relevant in normal venous thrombosis and critical in atherosclerotic conditions. A purification scheme was devised to obtain vascular versicans, which by biochemical, immunochemical, and ultrastructural means were asserted to be 1) composed primarily of isoforms V1 and V2; 2) free of contaminants; 3) prevalently substituted with chondroitin-4-sulfate and dermatan sulfate (DS) chains; and 4) capable of binding hyaluronan to form link protein-stabilized ternary complexes. Real-time analysis of human platelet perfused under diverse shear forces showed that they largely failed to bind to several vascular and nonvascular proteoglycans (PGs). In contrast, they bound in a dose- and shear rate-dependent manner to vascular versicans, exhibiting a unique attachment-detachment kinetics and establishing a firm substrate tethering characterized with no significant aggregation. Digestion of these PGs with lyases and competition experiments with purified glycosaminoglycans revealed that platelet adhesion to vascular versicans was primarily mediated by their DS chains. Incorporation of the versicans into fibrillar collagen substrates augmented their adhesive activity and strongly promoted platelet aggregation at low and high shear rates. Affinity chromatography of platelet surfaces on DS columns identified a 120–140 kDa polypeptide complex that behaved as a specific vascular versican binding membrane ligand in solid-phase binding assays. These findings indicate that selective versican variants of the subendothelium may serve as ancillary GPIb
/integrin/selectin-independent platelet ligands in healthy and diseased vascular beds and may be directly responsible for the platelet accruing after rupture of atherosclerotic plaques.—Mazzucato, M., Cozzi, M. R., Pradella, P., Perissinotto, D., Malmström, A., Mörgelin, M., Spessotto, P., Colombatti, A., De Marco, L., Perris, R. Vascular PG-M/versican variants promote platelet adhesion at low shear rates and cooperate with collagens to induce aggregation.
Key Words: proteoglycan • hemostasis • shear stress
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  Y. Nakashima, T. N. Wight, and K. Sueishi Early atherosclerosis in humans: role of diffuse intimal thickening and extracellular matrix proteoglycans Cardiovasc Res, July 1, 2008; 79(1): 14 - 23. [Abstract] [Full Text] [PDF]
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 T. N. Wight and M. J. Merrilees Proteoglycans in Atherosclerosis and Restenosis: Key Roles for Versican Circ. Res., May 14, 2004; 94(9): 1158 - 1167. [Abstract] [Full Text] [PDF]
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