Vascular PG-M/versican variants promote platelet adhesion at low shear rates and cooperate with collagens to induce aggregation

Mario Mazzucato, Maria Rita Cozzi, Paola Pradella, Daniela Perissinotto, Anders Malmström, Matthias Mörgelin, Paola Spessotto, Alfonso Colombatti, Luigi De Marco, Roberto Perris

Research output: Contribution to journalArticle

Abstract

We have identified a novel von Wille-brand 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 GPIbα/integrin/selectin-independent platelet ligands in healthy and diseased vascular beds and may be directly responsible for the platelet accruing after capture of atherosclerotic plaques.

Original languageEnglish
Pages (from-to)1903-1916
Number of pages14
JournalFASEB Journal
Volume16
Issue number14
DOIs
Publication statusPublished - Dec 2002

Keywords

  • Hemostasis
  • Proteoglycan
  • Shear stress

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

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    Mazzucato, M., Cozzi, M. R., Pradella, P., Perissinotto, D., Malmström, A., Mörgelin, M., Spessotto, P., Colombatti, A., De Marco, L., & Perris, R. (2002). Vascular PG-M/versican variants promote platelet adhesion at low shear rates and cooperate with collagens to induce aggregation. FASEB Journal, 16(14), 1903-1916. https://doi.org/10.1096/fj.02-0382com