This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Sickle cell anemia (homozygous hemoglobin SS) is characterized by both acute vaso-occlusive events and chronic vasculopathy. The chronic vascular lesions are manifest by intimal proliferation and arterial stenosis that are histologically similar to those in atherosclerosis, restenosis after angioplasty, and idiopathic moyamoya syndrome. Remarkably, these vascular lesions occur in the absence of conventional risk factors such as dyslipidemia, smoking, diabetes or hypertension, and contribute to the pathogenesis of stroke, pulmonary hypertension, retinopathy and renal failure in sickle cell anemia, often beginning in childhood. Despite the importance of this pathologic process, the identity of specific molecules and cognate mechanisms responsible for vascular lesions in sickle cell anemia are unknown, and are therefore the focus of this application. Current models of intimal proliferation suggest that vessel injury causes inflammation and production of growth factors that stimulate proliferation of resident vascular smooth muscle cells within the medial layer and migration into the intimal layer. The specific factors and underlying mechanisms for arterial injury and intimal proliferation in sickle cell anemia are poorly defined. Bone marrow-derived endothelial progenitor cells (EPCs) home to sites of vascular injury and have been implicated in repair. Simper and colleagues have recently characterized EPC-like cells that differentiate into smooth muscle cells when cultured with platelet-derived growth factor 1. Thus, EPCs may have at least a bi-potential capacity to differentiate into endothelial or smooth muscle cells. Thus far, the number, phenotype and lineage fate of EPCs in individuals with sickle cell anemia remains unknown. Our preliminary studies demonstrate markedly higher number of EPC colonies in children with sickle cell anemia compared to a control cohort. Further studies demonstrate that plasma levels of angiogenic cytokines erythropoietin and angiopoietin-2 levels were higher, whereas leptin level was lower in sickle cell anemia subjects relative to controls. Chronically transfused sickle cell anemia subjects had intermediate erythropoietin levels and EPC colony numbers, probably due to suppression of erythropoeisis. Given that Ang-2 destabilizes blood vessels and erythropoietin stimulates smooth muscle cell proliferation, we propose that EPC-mediated vascular repair is dysregulated in sickle cell anemia. Indeed, it is likely that EPCs preferentially differentiate into smooth muscle cells, which contribute to the intimal proliferative lesions typical of the vasculopathy in sickle cell anemia. The altered plasma milieu in sickle cell anemia is likely to promote arterial stiffness, via reduced nitric oxide and erythropoietin-induced expression of endothelin-1. Hypotheses To further the understanding of mechanisms underlying the pathophysiology of intimal proliferation in sickle cell anemia, we will test the following two hypotheses: 1. There is impairment of neo-vascularization attributes of endothelial progenitor cells which contributes to the chronic vasculopathy of sickle cell anemia. 2. The altered plasma milieu of sickle cell anemia causes abnormal arterial stiffness, and the degree of abnormality will correlate with the presence of overt vascular complications such as stroke or pulmonary hypertension.
Specific Aims 1. Confirm the unique profile of plasma angiogenic growth factors in sickle cell disease and determine its impact on EPC migration, tube formation and lineage commitment. 2. Determine whether migration and vascular tube formation of EPCs derived from subjects with sickle cell anemia is innately abnormal. 3. Examine the commitment of EPCs from subjects with sickle cell anemia towards the endothelial and smooth muscle cell lineages. 4. Define patterns of arterial stiffness in healthy controls and children with sickle cell anemia, and their relationship to EPC number, function, and angiogenic growth factor levels.
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