Research Article: Elevated Circulating Angiogenic Progenitors and White Blood Cells Are Associated with Hypoxia-Inducible Angiogenic Growth Factors in Children with Sickle Cell Disease

Date Published: May 23, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Solomon F. Ofori-Acquah, Iris D. Buchanan, Ifeyinwa Osunkwo, Jerry Manlove-Simmons, Feyisayo Lawal, Alexander Quarshie, Arshed A. Quyyumi, Gary H. Gibbons, Beatrice E. Gee.


We studied the number and function of angiogenic progenitor cells and growth factors in children aged 5–18 years without acute illness, 43 with Hemoglobin SS and 68 with normal hemoglobin. Hemoglobin SS subjects had at least twice as many mononuclear cell colonies and more circulating progenitor cell than Control subjects. Plasma concentrations of erythropoietin, angiopoietin-2, and stromal-derived growth factor (SDF)-1α were significantly higher in children with Hemoglobin SS compared to Control subjects. In a multivariate analysis model, SDF-1α concentration was found to be associated with both CPC number and total white blood cell count in the Hemoglobin SS group, suggesting that SDF-1α produced by ischemic tissues plays a role in mobilizing these cells in children with Hemoglobin SS. Despite having a higher number of angiogenic progenitor cells, children with Hemoglobin SS had slower migration of cultured mononuclear cells.

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Sickle cell anemia (Hemoglobin SS) is characterized by hemoglobin polymerization and the formation of inflexible sickled erythrocytes. Accumulation of sickled erythrocytes in the microcirculation causes acute vaso-occlusive events that lead to pain and acute organ injury. Chronic arterial vasculopathy, with intimal proliferation and arterial stenosis, can lead to complications such as stroke and pulmonary hypertension. The etiology of arterial stenosis in sickle cell anemia is poorly understood. We hypothesize that intimal proliferation in sickle cell anemia is due to abnormal reparative responses to ongoing vessel injury. Hemolytic anemia, vaso-occlusion, and abnormal flow dynamics in sickle cell anemia may contribute to vessel injury. Chronic intravascular hemolysis releases free heme, which binds avidly to nitric oxide (NO), causing NO depletion, and subsequent vaso-constriction and inflammation [1]. Erythrocyte-derived reactive iron and oxygen species are also directly injurious to endothelium [2]. Repetitive episodes of acute vaso-occlusion cause tissue ischemia and reperfusion, which also lead to inflammation and increased oxidative stress [3]. Evidence of ongoing inflammation and vascular injury is present in people with sickle cell anemia even when asymptomatic, with elevated levels of high sensitivity C-reactive protein (hsCRP) [4] and circulating endothelial cells [5].

A total of 111 children were studied, 68 Controls and 43 with Hemoglobin SS. Clinical features are shown in Table 1. As expected, children with Hemoglobin SS had significantly lower hemoglobin concentration, and higher white blood cell and platelet counts than Controls. There were no significant differences in age or sex between the two groups.

Vascular complications of sickle cell anemia, such as stroke and pulmonary hypertension, begin in childhood and are characterized by early development of intimal proliferation in cerebral and pulmonary arteries in the absence of cardiovascular risk factors, such as hypertension or hyperlipidemia. The mechanisms linking the primary genetic mutation in β-globin structure to the development of intimal proliferation and arterial stenosis are unknown. We hypothesize that sickle cell anemia is associated with abnormal vascular repair.

We found angiogenic CPC number to be elevated in this group of asymptomatic children with Hemoglobin SS, while mononuclear cell migration was slower than in healthy Control children. Stromal-derived factor-1α, a hypoxia-inducible angiogenic growth factor, is strongly associated with the elevated numbers of CPCs and total WBC in children with Hemoglobin SS. Tissue ischemia resulting from vaso-occlusion may promote both proangiogenic and proinflammatory states in sickle cell disease.




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