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Selectin-Targeting Peptide–Glycosaminoglycan Conjugates Modulate Neutrophil–Endothelial Interactions

  • Author(s): Wodicka, JR
  • Morikis, VA
  • Dehghani, T
  • Simon, SI
  • Panitch, A
  • et al.
Abstract

© 2018, The Author(s). Introduction: The glycocalyx is a layer of glycoproteins, proteoglycans and glycosaminoglycans that coats the luminal surface of most blood vessels. It effectively regulates adhesive interactions between leukocytes in flowing blood and the endothelium, where during inflammation, binding to E- and P-selectins and intercellular adhesion molecule-1 (ICAM-1) promotes cell tethering and arrest under shear flow. Methods: In this study, we examine the targeting of E-selectin by an engineered peptide moiety bound to a dermatan sulfate backbone. We further investigate this conjugate, denoted as EC-SEAL, by observing its binding to inflamed endothelium, and quantifying its ability to modulate neutrophil–endothelium interactions. Results: Binding data reveal that EC-SEAL recognizes domains on E-selectin, and to a lesser degree on P- and L-selectin, and ICAM-1. Further, EC-SEAL increases neutrophil rolling velocity, and decreases neutrophil arrest and migration on inflamed human microvascular endothelial cells under physiologically relevant flow conditions. Conclusions: We conclude that simple targeting strategies can mimic glycocalyx function under inflammatory conditions, effectively reducing neutrophil recruitment.

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