2008
DOI: 10.1172/jci33308
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Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease

Abstract: Patients with sickle-cell disease (SCD) suffer from tissue damage and life-threatening complications caused by vasoocclusive crisis (VOC). Endothelin receptors (ETRs) are mediators of one of the most potent vasoconstrictor pathways in mammals, but the relationship between vasoconstriction and VOC is not well understood. We report here that pharmacological inhibition of ETRs prevented hypoxia-induced acute VOC and organ damage in a mouse model of SCD. An in vivo ultrasonographic study of renal hemodynamics show… Show more

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Cited by 120 publications
(136 citation statements)
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“…This is also correct. Published data evidence the involvement of oxidative stress (79,100,105,108,113,115,116,121,123,132,134,135), inflammation (9, 22, 27, 32, 101, 105-108, 115, 124-127, 134), dyslipidemia (135)(136)(137)(138), microparticles (89,122,123,139), and vasoactive peptides (110,111,(140)(141)(142)(143). These additional pathways (depicted in Figure 2) are potentially additive or synergistic to intravascular hemolysis-like mechanisms.…”
Section: Controversies Regarding the Hyperhemolysis Modelmentioning
confidence: 99%
“…This is also correct. Published data evidence the involvement of oxidative stress (79,100,105,108,113,115,116,121,123,132,134,135), inflammation (9, 22, 27, 32, 101, 105-108, 115, 124-127, 134), dyslipidemia (135)(136)(137)(138), microparticles (89,122,123,139), and vasoactive peptides (110,111,(140)(141)(142)(143). These additional pathways (depicted in Figure 2) are potentially additive or synergistic to intravascular hemolysis-like mechanisms.…”
Section: Controversies Regarding the Hyperhemolysis Modelmentioning
confidence: 99%
“…In addition, the abnormally activated ET-1 system and the reduced NO bioavaibility associated with activated endothelial vascular cells, highly adherent neutrophils and dense, dehydrated sickle red cells, all participate in sickle cell-related tissue injury. 4,16,17 Although the liver is not one of the main target organs of SCD, its anatomic organization and function, characterized by a sluggish circulation, high metabolic rate and complex regulation of blood flow in the microcirculation, make this an interesting "window organ" to study the pathogenesis of sickle cell-related tissue damage.…”
Section: Introductionmentioning
confidence: 99%
“…17 By competing with RBC membrane-associated ICAM-4 for binding to endothelial aVβ3 integrins, soluble ICAM-4 might reduce red cell/endothelium interactions thereby moderating an otherwise exaggerated adhesiveness of SS RBC to the vascular wall. The reduced level of CD36 on SAD RBC could result from the high plasma level of endothelin-1 found in both SS patients and SAD mice, 34,35 which decreases CD36 protein expression, an effect recently reported for vascular smooth muscle cells. 36 In conclusion, the present work shows an over-adhesiveness to endothelium of SAD mouse RBC, with this phenomenon depending on two adhesion proteins, ICAM-4 and CD36, as previously reported for human SS RBC.…”
Section: Discussionmentioning
confidence: 71%