Circulating Activated Endothelial Cells in Sickle Cell Anemia

Solovey, Anna; Lin, Yi; Browne, Paul; Choong, Stephana; Wayner, Elizabeth A.; Hebbel, Robert P.

doi:10.1056/nejm199711273372203

Cited by 589 publications

(474 citation statements)

References 25 publications

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“…Circulating endothelial cells from SCD patients present an abnormal expression of VCAM-1, ICAM-1, and E-selectin [3]. The increases observed in sVCAM-1 and sICAM-1 levels probably reflect an increased level of endothelial cell adhesion molecule expression and activation in patients and an increased capacity for the adhesion of sickle erythrocytes and leukocytes to the endothelium.…”

Section: Discussionmentioning

confidence: 97%

“…The vascular endothelium appears to be abnormally activated in SCD; for example, circulating endothelial cells (CEC) demonstrate increased expression of the adhesion molecules, VCAM-1, ICAM-1, and E-selectin [3]. VCAM-1 binds the integrin, VLA-4, (expressed by sickle erythrocytes), and its expression on endothelial cells may be stimulated by cytokines.…”

Section: Introductionmentioning

confidence: 99%

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Increased levels of soluble ICAM‐1 in the plasma of sickle cell patients are reversed by hydroxyurea

et al. 2004

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Increased adhesive events between the blood vessel endothelium and red and white cells play a central role in the initiation of vasoocclusive crisis in sickle cell disease (SCD). Soluble VCAM-1 levels are increased in the plasma of sickle cell patients and may be reduced during hydroxyurea (HU) therapy. Reports regarding any changes in soluble ICAM-1 (sICAM-1) levels in sickle cell patients, however, are conflicting, and as yet no beneficial effect of HU upon levels has been observed. Thus, we sought to thoroughly investigate changes in sICAM-1 levels in SCD patients and the effect of HU therapy (20-30 mg/kg/day). Plasma sVCAM-1 levels were significantly higher in steady-state SCD patients than in normal controls (766 ± 86 ng/mL vs. 325 ± 38 ng/mL, respectively, P < 0.0001). sVCAM-1 levels were decreased in patients on HU therapy (543 ± 69 ng/mL) compared to those not taking HU; however, this difference was not significant. Plasma sICAM-1 levels were significantly increased in steady-state SCD patients compared to normal individuals (285 ± 20 ng/mL vs. 202 ± 16 ng/mL, respectively, P = 0.002), and HU therapy significantly reduced sICAM-1 levels in patients (217 ± 12, P = 0.027) to levels approaching those of healthy individuals. sVCAM-1 levels inversely correlated with fetal hemoglobin levels in SCD patients, while a nonsignificant inverse trend was observed between sICAM-1 levels and fetal hemoglobin. In conclusion, plasma sICAM-1 levels were significantly increased in SCD patients, and this increase was reversed by hydroxyurea therapy, possibly reflecting reduced endothelial activation in patients taking HU. Such an event may benefit patients by reducing adhesive interactions between white cells and the endothelium. Am.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Increased levels of soluble ICAM‐1 in the plasma of sickle cell patients are reversed by hydroxyurea

et al. 2004

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“…CECs were defined as negative for CD45 and positive for CD34 and P1H12 (9,25). Activated CECs were defined as negative for CD45, positive for P1H12, and positive for CD62 or CD106 (9,25).…”

Section: Methodsmentioning

confidence: 99%

“…In humans, CECs have been detected in diverse conditions having in common endothelial damage, such as coronary angioplasty, acute coronary syndrome, sickle cell anemia, thrombotic thrombocytopenic purpura, infection with Rickettsia conorii or cytomegalovirus, Behçet's disease, systemic lupus erythematosus (SLE), and small-vessel vasculitis (7)(8)(9)(10)(11)(12)(13)(14)(15). Moreover, it has been suggested that in response to severe ischemia or cytokine stimuli, circulating endothelial cell progenitors (CEPs) increase and home into sites of angiogenesis and/or vascular damage, and consequently contribute to neovascularization and/or wound-healing processes (16)(17)(18).…”

Section: Conclusion the Presence Of Cecs In Patientsmentioning

confidence: 99%

Circulating endothelial cells as a marker of ongoing vascular disease in systemic sclerosis

Papa

Colombo

Fracchiolla

et al. 2004

Arthritis & Rheumatism

136

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Results. Total and activated CEC counts were significantly higher in SSc patients compared with healthy controls and were positively correlated with the disease activity score. With respect to visceral involvement, significant correlation was observed between the CEC number and the severity of pulmonary hypertension. High levels of endothelial progenitors were observed in patients with SSc, and the counts were higher in the early stages of disease.

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“…13 Variations in these signals can affect the EC characteristics and thereby contribute to the unpredictable occurrences of VOC. The resulting endothelial injury, indicated by the presence of activated ECs circulating in the blood of SCA patients, 14 could contribute to additional complications. Here, we evaluate the effects of HU on vascular ECs.…”

Section: Introductionmentioning

confidence: 99%

Hydroxyurea downregulates endothelin-1 gene expression and upregulates ICAM-1 gene expression in cultured human endothelial cells

et al. 2003

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The clinical efficacy of oral hydroxyurea (HU) in adults and children with sickle cell anemia (SCA) cannot solely be explained by its ability to enhance fetal hemoglobin (HbF) expression. Since increased adherence of sickle red blood cells to vascular endothelium is a possible contributing factor to vasoocclusive crisis (VOC), we explored the effect of HU on human endothelial cell (EC) lines (TrHBMEC and EA-hy 926). We demonstrated that HU, in a dose-dependent and reversible manner, significantly decreased (up to threefold) the release of endothelin-1 (ET-1), a vasoconstrictor peptide through downregulation (up to three-fold) of ET-1 gene expression. This finding is of therapeutic relevance as SCA patients exhibit elevated serum levels of ET-1 during episodes of VOC and levels correlate with disease severity. Unexpectedly, HU upregulated (up to three-fold) the expression of membrane-bound intercellular cell adhesion molecule 1 (mbICAM-1) and its soluble form (sICAM-1) with a parallel increase in ICAM-1 mRNA expression. Although ICAM-1 does not appear to be involved in the sickle cell adhesion to vascular endothelium, it may exacerbate vaso-occlusion by promoting leukocyte adhesion. The HU-induced increase in mbICAM-1 may appear inconsistent with the clinical benefits confered by HU. However, both the increase in sICAM-1-and HU-induced leukocyte reduction in patients, may counteract the potentially detrimental effect of elevated mbICAM-1 expression. Also HU reduces the expression of vascular cell adhesion molecule (VCAM-1) on EC. Since HU reduces the very late antigen 4-positive reticulocytes in SCA patients, a ligand for VCAM-1, HU-induced downregulation of VCAM-1 on EC will very likely decrease the reticulocyte-endothelium adhesion. Thus, HU, apart from inducing HbF expression in the red cell, also affects the expression profile of EC compartment.

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Circulating Activated Endothelial Cells in Sickle Cell Anemia

Abstract: Our studies suggest that the vascular endothelium is activated in patients with sickle cell anemia, regardless of the patients' clinical status. Adhesion proteins on activated endothelial cells may have a role in the vascular pathology of sickle cell disease.

Cited by 589 publications

References 25 publications

Increased levels of soluble ICAM‐1 in the plasma of sickle cell patients are reversed by hydroxyurea

Increased levels of soluble ICAM‐1 in the plasma of sickle cell patients are reversed by hydroxyurea

Circulating endothelial cells as a marker of ongoing vascular disease in systemic sclerosis

Hydroxyurea downregulates endothelin-1 gene expression and upregulates ICAM-1 gene expression in cultured human endothelial cells

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