Sickle Red Cell–Endothelium Interactions

Abstract

Periodic recurrence of painful vaso-occlusive crisis is the defining feature of sickle cell disease. Among multiple pathologies associated with this disease, sickle-red cell-endothelium interaction has been implicated as potential initiating mechanism in vaso-occlusive events. This review focuses on various interrelated mechanisms involved in human sickle red cell adhesion. We discuss in vitro and microcirculatory findings on sickle red cell adhesion, its potential role in vasoocclusion, and the current understanding of receptor-ligand interactions involved in this pathological phenomenon. In addition, we discuss the contribution of other cellular interactions (leukocytes recruitment and leukocyte-red cell interaction) to vaso-occlusion as observed in transgenic sickle mouse models. Emphasis is given to recently discovered adhesion molecules that play a predominant role in mediating human sickle red cell adhesion. Finally, we analyze various therapeutic approaches for inhibiting sickle red cell adhesion by targeting adhesion molecules, and also consider therapeutic strategies that target stimuli involved in endothelial activation and initiation of adhesion.

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“…Though, recent advances in SCD research have revealed a more complex pathophysiology of the disease [2][3][4]. Indeed, it has been demonstrated that inflammation and increased leukocyte-erythrocyte-endothelial interactions are the major potential initiating mechanisms of recurrent occlusion of blood vessels [5,6].…”

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“…The RBC membrane receptors VLA-4/α4β1 bind to endothelial receptors directly to vascular cell adhesion molecule 1 (VCAM-1) and interacts with subendothelial matrix proteins (BCAM/LU, α4β1 with the laminin and VWF) [37,38]. Red blood cell interactions with the vascular endothelium also lead to the production of oxygen radicals by activating transcription factor NF-κB.…”

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“…Mechanistically, the interaction between the erythrocytes and the endothelium involves α4β1 integrin, expressed on the erythrocyte surface, and fibronectin, vascular cell adhesion protein 1 (VCAM-1), intracellular adhesion molecule 1 (ICAM-1), and E-selectin, expressed on the endothelial cell surface [19]. Other ligands, including thrombospondin, von Willebrand factor, immunoglobulins, and fibrinogen, also seem to contribute to this adherence [20].…”