Redox-dependent impairment of vascular function in sickle cell disease

Abstract

The vascular pathophysiology of sickle cell disease (SCD) is influenced by many factors, including adhesiveness of red and white blood cells to endothelium, increased coagulation, and homeostatic perturbation. The vascular endothelium is central to disease pathogenesis because it displays adhesion molecules for blood cells, balances procoagulant and anticoagulant properties of the vessel wall, and regulates vascular homeostasis by synthesizing vasoconstricting and vasodilating substances. The occurrence of intermittent vascular occlusion in SCD leads to reperfusion injury associated with granulocyte accumulation and enhanced production of reactive oxygen species. The participation of nitric oxide (NO) in oxidative reactions causes a reduction in NO bioavailability and contributes to vascular dysfunction in SCD. Therapeutic strategies designed to counteract endothelial, inflammatory, and oxidative abnormalities may reduce the frequency of hospitalization and blood transfusion, the incidence of pain, and the occurrence of acute chest syndrome and pulmonary hypertension in patients with SCD.

Figure 1

Increased red cell adhesion in sickle cell disease. Lu gp, Lutheran glycoprotein; PMN, polymorphonuclear leukocytes;VCAM-1, vascular cell adhesion molecule-1; vWF, von Willebrand factor.

Figure 2

Vascular inflammation in sickle cell disease. PMN, polymorphonuclear leukocytes; IL-1, interleukin-1; IL-6, interleukin-6; IL-8, interleukin-8; TNF-α, tumor necrosis factor-alpha; PGSL-1, P-selectin glycoprotein ligand-1; Fcγ, high-affinity Fc gamma receptor; ICAM-1, intercellular adhesion molecule-1.

Figure 3

Pathogenesis of increased coagulant activity in sickle cell disease.

Figure 4

Increased intravascular consumption of nitric oxide in sickle cell disease. Superoxide (O₂^•−) generated by uncoupled endothelial nitric oxide synthase (eNOS), xanthine oxidase (XO) and NADPH oxidase, reacts with nitric oxide (NO) to form peroxynitrite (ONOO ⁻). Nitric oxide is also consumed by plasma free hemoglobin, released by intravascular hemolysis.