Microvascular Abnormalities in SSc

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The prevalence of RP in the general UK population is estimated to be approximately 14 percent. The majority of these patients (95 percent) are classified as having primary RP, a benign though painful condition with no associated structural damage and abnormalities to the microvessels and that will not develop any associated connective tissue disease.

However, in more than 90 percent of SSc patients, RP is frequently the first reported symptom of underlying connective tissue disease and appears to be a unifying characteristic across a heterogeneous disease spectrum; it is therefore likely to be of etiological significance. The presence of RP in SSc patients is associated with irreversible tissue damage, capillary dilation and dropout, and structural damage to the digital microvasculature. In SSc, microvascular damage appears to be a systemic phenomenon, as affected internal organs also show significantly perturbed blood flow. Ultra-structurally, endothelial cells (ECs) show evidence of vacuolization, nuclear degeneration, loss of cell-cell contacts, and multilayering of the basement membrane prior to the onset of fibrosis [2]. Serum and plasma levels of factors considered to be markers of endothelial activation such as von Willebrand factor, adhesion molecules, and endothelin-1 (ET-1) are all increased in SSc patients. However, it can be argued that soluble levels of these factors may reflect activation of cell types other than endothelial cells. More relevant are in situ analyses of SSc skin and other affected organs that have shown increased expression of adhesion molecules, endothelin (ET)-1, platelet-derived growth factor-B (PDGF-B), and transforming growth factor (TGF)-b by endothelial cells. A stimulus of early endothelial cell activation in SSc is likely to be ischemic associated hypoxia, which is known to have profound effects on endothelial cell metabolism. Hypoxia has been shown to rapidly induce the synthesis by cultured endothelial cells of adhesion molecules and key inflammatory cytokines and growth factors.

Anti-endothelial cell autoantibodies (AECAs) may also be responsible for regulating endothelial cell phenotype in SSc. AECAs have been detected in the sera of SSc patients

Figure 1 Fibrosis and scar formation is a multistage process involving complex interactions between numerous participating cell types. Pericytes are intimately associated with this process. Preceding transmigration of monocytes is an increase in vascular permeability, brought about by a change in the interactions between endothelial cells and pericytes. Pericytes are also known to produce profibrotic growth factors that can directly modulate fibroblast function and biosynthetic profile. Finally, pericytes are considered mesenchymal precursor cells and as such can transdifferentiate directly into matrix-synthesizing myofibroblasts. (see color insert)

Figure 1 Fibrosis and scar formation is a multistage process involving complex interactions between numerous participating cell types. Pericytes are intimately associated with this process. Preceding transmigration of monocytes is an increase in vascular permeability, brought about by a change in the interactions between endothelial cells and pericytes. Pericytes are also known to produce profibrotic growth factors that can directly modulate fibroblast function and biosynthetic profile. Finally, pericytes are considered mesenchymal precursor cells and as such can transdifferentiate directly into matrix-synthesizing myofibroblasts. (see color insert)

with a prevalence of up to 50 percent, suggesting that the microvasculature maybe the target of an autoimmune response. Although the antigens to which they bind appear to be heterogeneous within and between sera, it is known that AECA can induce pathogenic changes in endothelial cells in vitro, such as increased leukocyte adhesion, and secretion of inflammatory cytokines, such as interleukin (IL)-1. More recently, autoimmune sera from SSc patients have been shown to cross-react with both the human cytomegalovirus late protein UL94 and SSc associated autoantigens, such as fibrillarin and heterogeneous nuclear ribonucleoprotein. Therefore molecular mimicry of cyto-megalovirus may trigger an SSc associated autoimmune response and result in endothelial cell activation and apop-tosis. Increased endothelial cell apoptosis has been shown to occur in vivo, prior to the onset of fibrosis in both human SSc tissue and in the UCD 2000 avian model of SSc, an animal model of SSc that shows similar vascular abnormalities.

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