Mechanism of interaction of thrombospondin with human endothelium and inhibition of sickle erythrocyte adhesion to human endothelial cells by heparin

Kalpna Gupta, Pankaj Gupta, Anna Solovey, Robert P. Hebbel

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49 Scopus citations

Abstract

Thrombospondin (TSP) mediates sickle erythrocyte adhesion to endothelium, but the mechanism remains unknown. Since TSP is comprised of heterogeneously distinct domains, this adhesion may depend on the interaction of specific regions of TSP with different cell surface receptors. To examine the mechanisms of interaction of TSP with human umbilical vein endothelial cells (HUVEC), we performed binding studies using soluble [125I]TSP. Our data showed that (i) monoclonal antibodies (MoAbs) against cell surface heparan sulfate (HS) or the heparin-binding domain of TSP, or cleavage of HS on HUVEC by heparitinase reduced TSP binding by 28-40%, (ii) the RGD peptide or MoAbs against integrin α(v)β3 or the calcium binding region of TSP inhibited binding by 18-28%, and (iii) a MoAb against the cell-binding domain of TSP inhibited binding by 36%. Unmodified heparin inhibited the binding of TSP to endothelial cells by 70% and did so far more effectively than selectively desulfated heparins, HS or chondroitin sulfate. Heparin inhibited TSP binding to HUVEC at much lower concentrations than were required to inhibit TSP binding to sickle erythrocytes. Unmodified heparin effectively inhibited the TSP-mediated adhesion of sickle erythrocytes to HUVEC. These data imply that cell surface HS-mediated mechanisms play a key role in TSP-mediated sickle erythrocyte adhesion to endothelium, and heparin may be of use for inhibition of this adhesion. Copyright (C) 1999 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)63-73
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1453
Issue number1
DOIs
StatePublished - Jan 6 1999

Bibliographical note

Funding Information:
This study was supported by National Institutes of Health Grant HL30160, and the United States Department of Veterans Affairs. We thank Jill Weber and Rokhsana Patel for technical assistance, and Jeanne Harkness for assistance in obtaining blood samples.

Keywords

  • Adhesion
  • Endothelium
  • Heparan sulfate
  • Heparin
  • Sickle cell disease
  • Thrombospondin

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