Vasoactive factors in sickle cell disease: In vitro evidence for endothelin‐1‐mediated vasoconstriction

Abstract

While systemic plasma endothelin-1 (ET-1) levels are increased during acute crisis in sickle cell disease, the relative levels of potent vasoactive factors that contribute to the regulation of vascular function, such as ET-1, NO, and cell-free hemoglobin, during the course of periodic vaso-occlusive episodes remain unclear. Moreover, whether and to what extent sickling-induced release of ET-1 alters vascular tone is not completely understood. To investigate the sequential changes in circulating vasoactive factors, we measured plasma ET-1, NO metabolites (NOx), and cell-free hemoglobin (Hb) before (steady-state), during (crisis), and after a vaso-occlusive (post-crisis) episode. Steadystate ET-1 levels (fmol/mL) increased from 2.3 ± 0.4 to 11.0 ± 1.4 and 4.2 ± 1.0 during crisis and post-crisis periods, respectively. There was no significant difference in plasma NOx levels. Cell-free Hb levels were significantly higher in sickle cell patients in all phases as compared to the control group, and especially during crisis cell-free Hb levels were elevated by 4-fold (209,000 ± 31,000 vs. 46,000 ± 5,300 ng/mL in steady-state). Conditioned medium from human pulmonary artery endothelial cells exposed to sickled erythrocytes prepared by deoxygenation induced contraction of aortic rings, and this effect was blocked by an ET A receptor antagonist. These findings indicate that ET-1 is the predominant contractile factor released by cultured endothelial cells upon exposure to deoxygenated sickled SS erythrocytes and ET-1-NO-NO scavenger balance is altered in favor of vasoconstriction during an acute episode in SCD. Am.

Cellular, Pharmacological, and Biophysical Evaluation of Explanted Lungs from a Patient with Sickle Cell Disease and Severe Pulmonary Arterial Hypertension

“…Endothelin markers have been linked to preclinical murine models of SCD and to human sickle cell red blood cells, 62 and changes in plasma ET-1 levels are associated with clinical changes in disease. 63,64 It was not known whether upregulation of endothelin in the blood extended to human SCD-associated PAH lungs and vascular cells from the same. Analysis of parenchyma, proximal and distal pulmonary arteries, and PASMCs from SCD-associated PAH lungs revealed significant upregulation of the ET-1-ETA signaling axis at multiple anatomic locations.…”

Cardiopulmonary Complications of Sickle Cell Disease: Role of Nitric Oxide and Hemolytic Anemia

“…[25][26][27] In vitro, sickle erythrocytes increase endothelin-1 production by cultured human endothelial cells and endothelin receptor A antagonism decreases the vasoconstrictive effects of conditioned media from pulmonary endothelial cells exposed to sickled erythrocytes on aortic rings. 28 In addition, endothelin-1 activates Gardos channels in human sickle erythrocytes, an effect that may promote sickle cell dehydration and facilitate red blood cell sickling and adhesion. 29…”

Sodium phenyl butyrate downregulates endothelin‐1 expression in cultured human endothelial cells: Relevance to sickle‐cell disease

“…Abnormalities of the vascular tone regulation and increased RBC adhesion to the endothelium have been shown to be major participants to the initiation of vaso-occlusion in SCD [18]. ET-1 is a major factor of vasoconstriction [19] and smooth muscle proliferation, which is produced by ECs after hypoxia and/or ischemia [20]. It is increased in SCD, particularly during vaso-occlusive crises [19,21] or acute chest syndrome [22], and reduced in HUtreated patients [23].…”

“…ET-1 is a major factor of vasoconstriction [19] and smooth muscle proliferation, which is produced by ECs after hypoxia and/or ischemia [20]. It is increased in SCD, particularly during vaso-occlusive crises [19,21] or acute chest syndrome [22], and reduced in HUtreated patients [23]. Levels of soluble endotheliumderived adhesion molecules in patients with SCD are associated with pulmonary hypertension, organ dysfunction and mortality [24].…”