Model of sickle cell-endothelial cell adhesion

Sickle red cells (RBCs) are shown here as red biconcave ovals and the vascular endothelium as a layer of gray elongated flat cells. Three steps of adhesion are shown: (A) Initial contact, (B) Rolling adhesion, and (C) Firm adhesion. Initial contact of sickle RBCs with endothelium is through binding of an erythroid P-selectin ligand with endothelial cell P-selectin. The interaction of E-selectin with a sialylated carbohydrate RBC ligand also participates in initial adhesion. These same molecules that initially slow flowing sickle cells also mediate their rolling along the vascular wall. Several ligand-receptor cognate pairs are involved in firm adhesion, which creates an adhesive nidus behind which rigid, sickled RBCs become trapped. Some of these are shown in this diagram. CD36 on the sickle RBC binds to alphaVbeta3 integrin on the endothelial cell by using plasma thrombospondin (TSP) as a bridging molecule. The RBC integrin alpha4beta1 binds directly to vascular cell adhesion molecule-1 (VCAM-1). Activated endothelial cells express alpha5beta1 and additional alphaVbeta3 to which sickle cells stick. Gaps are created between activated endothelial cells, which expose adhesive subendothelial matrix proteins (laminin, TSP, von Willebrand Factor) that also bind sickle cells.