Regulation of glycoprotein VI-dependent platelet activation and thrombus formation by heparan sulfate proteoglycan perlecan

Provenzale, I., De Simone, I., Gibbins, J. M. ORCID: https://orcid.org/0000-0002-0372-5352, Heemskerk, J. W. M., van der Meijden, P. E. J. and Jones, C. I. ORCID: https://orcid.org/0000-0001-7537-1509 (2023) Regulation of glycoprotein VI-dependent platelet activation and thrombus formation by heparan sulfate proteoglycan perlecan. International Journal of Molecular Sciences, 24 (17). 13352. ISSN 1422-0067 doi: 10.3390/ijms241713352

Abstract/Summary

Proteoglycans form a heterogeneous family of proteins with covalently bound sulphated 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 α2β1. 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 αIIbβ3 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.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/113205
Identification Number/DOI	10.3390/ijms241713352
Refereed	Yes
Divisions	Life Sciences > School of Biological Sciences > Biomedical Sciences
Publisher	MDPI
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