Regulation of Glycoprotein VI-Dependent Platelet Activation and Thrombus Formation by Heparan Sulfate Proteoglycan Perlecan

Isabella Provenzale, Ilaria De Simone, Jonathan M. Gibbins, Johan W. M. Heemskerk*, Paola E. J. van der Meijden, Chris I. Jones*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Proteoglycans form a heterogeneous family of proteins with covalently bound sulfated glycosaminoglycans. The extracellular matrix proteoglycan perlecan has been proposed to bind to the platelet- and megakaryocyte-specific receptor G6bB, co-regulating platelet glycoprotein VI (GPVI) signaling. The derived non-sulfate proteoglycan endorepellin was previously shown to enhance platelet adhesion via the collagen receptor, integrin & alpha;2 & beta;1. Here, we compared the roles of perlecan and other matrix proteoglycans in platelet responses and thrombus formation. We used multi-color flow cytometry to measure the degranulation and integrin & alpha;IIb & beta;3 activation of washed platelets in response to various proteoglycans and collagen-related peptide (CRP), the GPVI agonist. Perlecan, but not endorepellin, enhanced the CRP-induced activation of platelets in a time- and concentration-dependent manner. Similar to collagen, immobilized perlecan, but not other proteoglycans, supported static platelet adhesion and spreading. In-flowed whole-blood perlecan diminished shear-dependent platelet adhesion, while it enforced GPVI-dependent thrombus formation-to a larger extent than endorepellin-to induce more contracted aggregates of activated platelets. We concluded that the sulfated proteoglycan perlecan enhances GPVI-dependent platelet responses extending to thrombus formation, but it does so at the expense of reduced adhesion of platelets under flow.
Original languageEnglish
Article number13352
Number of pages13
JournalInternational Journal of Molecular Sciences
Volume24
Issue number17
DOIs
Publication statusPublished - 1 Sept 2023

Keywords

  • collagen-related peptide
  • endorepellin
  • glycoprotein VI
  • perlecan
  • platelet spreading
  • proteoglycan
  • ACUTE CORONARY SYNDROMES
  • EXTRACELLULAR-MATRIX
  • MECHANISMS
  • ADHESION
  • RECEPTORS
  • PECAM-1
  • GPVI

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