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148 - Sickle Cell Disease Endothelial Activation and Dysfunction
- from PART III - VASCULAR BED/ORGAN STRUCTURE AND FUNCTION IN HEALTH AND DISEASE
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- By Robert P. Hebbel, Vascular Biology Center, University of Minnesota, Minneapolis
- Edited by William C. Aird, Harvard University, Massachusetts
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- Book:
- Endothelial Biomedicine
- Published online:
- 04 May 2010
- Print publication:
- 03 September 2007, pp 1352-1359
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- Chapter
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Summary
Sickle cell anemia is characterized by hemolytic anemia, acute painful episodes that are believed to be caused by vaso-occlusion, and various organ-specific complications (1). Although the fundamental molecular basis for this disease is the inherited presence of the mutant sickle hemoglobin, the pathogenesis of clinical sickle disease is exceedingly complex. The studies described here, both bedside-to-bench and bench-to-bedside, have suggested that the endothelium contributes substantially to the vascular pathobiology of sickle disease and helps govern clinical phenotype (2). Indeed, we regard sickle cell anemia as an “endothelial disease” in which the endothelium is abnormally activated and dysfunctional. It is likely that the vascular pathobiology of this disease is affected by the endothelial cell (EC)'s functions as a space-defining physical barrier, an adhesive surface, a regulator of vascular tone, a balancer of the anticoagulant and procoagulant properties of blood and vessel wall, a participant in the inflammatory response, and a responsive surface that is dynamically alterable.
THE BEGINNING: FROM BEDSIDE TO BENCH
After the first medical literature report of a patient with sickle disease in 1910 (3), early studies identified the relationship between deoxygenation and cytoplasmic changes and red cell sickling (4), and ultimately the molecular character of the disease as being caused by an abnormal hemoglobin molecule (5). Thereafter, the traditional view of sickle disease explained pathophysiology simply via the sickling phenomenon, a view we now recognize as being highly oversimplified (6). The bedside observation of marked heterogeneity in clinical phenotype, both from person-to-person and from time-to-time for any given patient, stimulated our original interest in the endothelial biology of this disease.
174 - Blood Endothelial Cells
- from PART IV - DIAGNOSIS AND TREATMENT
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- By Robert D. Simari, Mayo Clinic College of Medicine, Rochester, Minnesota, Rajiv Gulati, University of Birmingham, United Kingdom, Robert P. Hebbel, University of Minnesota Medical School, Minneapolis
- Edited by William C. Aird, Harvard University, Massachusetts
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- Book:
- Endothelial Biomedicine
- Published online:
- 04 May 2010
- Print publication:
- 03 September 2007, pp 1612-1620
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- Chapter
- Export citation
-
Summary
In 1963, in an attempt to define the source of endothelium on vascular grafts, Stump and colleagues suspended a Dacron patch within the lumen of a prosthetic vascular graft in the aorta of a juvenile pig (1). As early as 14 days following placement, islands of endothelial cells (ECs) were identified on the patch surface. Because the patch had been isolated from contact with both the prosthesis and native vascular tissue, these findings implicated circulating blood as the source of ECs. These observations were not actively pursued from an experimental or clinical context until recently.
This original observation of a vascular source of endothelium has been corroborated in chimeric transplantation models that have enabled the discrimination of host- and donor derived cells by genetic markers. These studies have revealed bone marrow–derived circulating progenitors to contribute to both endothelial and intimal smooth muscle cell formation in multiple models of vascular injury as reviewed by Sata (2). Moreover, treatment with 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) appears to accelerate the incorporation of bone marrow–derived ECs following arterial denudation in rodent models (3,4). These studies confirm the presence of cells with either an endothelial phenotype or endothelial potential within human blood. Furthermore, strategies have been developed to utilize these cells for the prevention and treatment of vascular disease. In this chapter, identification, classification, and potential translational uses of these cells will be discussed.
CIRCULATING ENDOTHELIAL CELLS
Definition and Phenotype
The blood of normal individuals contains circulating ECs (CECs) as well as monocytic cells with the potential to develop endothelial features in culture (culture-modified mononuclear cells – CMMCs) and progenitors capable of differentiation into ECs (so-called true endothelial progenitor cells [EPCs]).