title: Sickle cell disease vasculopathy: a state of nitric oxide resistance.
abstract: Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by microvascular vaso-occlusion with erythrocytes containing polymerized sickle (S) hemoglobin, erythrocyte hemolysis, vasculopathy, and both acute and chronic multiorgan injury. It is associated with steady state increases in plasma cell-free hemoglobin and overproduction of reactive oxygen species (ROS). Hereditary and acquired hemolytic conditions release into plasma hemoglobin and other erythrocyte components that scavenge endothelium-derived NO and metabolize its precursor arginine, impairing NO homeostasis. Overproduction of ROS, such as superoxide, by enzymatic (xanthine oxidase, NADPH oxidase, uncoupled eNOS) and nonenzymatic pathways (Fenton chemistry), promotes intravascular oxidant stress that can likewise disrupt NO homeostasis. The synergistic bioinactivation of NO by dioxygenation and oxidation reactions with cell-free plasma hemoglobin and ROS, respectively, is discussed as a mechanism for NO resistance in SCD vasculopathy. Human physiological and transgenic animal studies provide experimental evidence of cardiovascular and pulmonary resistance to NO donors and reduced NO bioavailability that is associated with vasoconstriction, decreased blood flow, platelet activation, increased endothelin-1 expression, and end-organ injury. Emerging epidemiological data now suggest that chronic intravascular hemolysis is associated with certain clinical complications: pulmonary hypertension, cutaneous leg ulcerations, priapism, and possibly stroke. New therapeutic strategies to limit intravascular hemolysis and ROS generation and increase NO bioavailability are discussed.
authors.affiliation: Vascular Medicine Branch, National Heart Lung Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Wood
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Hsu
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
mesh_terms: D000755:Anemia, Sickle Cell / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism; D006461:Hemolysis; D006801:Humans; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D014655:Vascular Resistance
chemical_list: D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III