Veterinary Science - Theses
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ItemVascular endothelial dysfunction in chronic inflammatory disease: modulatory effects of mesenchymal stem cells( 2014)Chronic inflammatory diseases represent an important and growing medical concern. Rheumatoid arthritis is a common chronic inflammatory disease, and afflicted patients suffer from a range of clinical cardiovascular diseases as co-morbidities. The initial cardiovascular change induced by systemic inflammation is endothelial dysfunction, caused by exposure of endothelial cells to circulating inflammatory mediators. Endothelial dysfunction is characterised by a shift in the phenotype of endothelial cells towards impaired vasodilation, increased pro-inflammatory actions, and pro-thrombotic properties. This study utilised an ovine collagen-induced model of arthritis to characterise the presence of endothelial dysfunction in arthritic sheep. Wire myography was used to assess endothelium-dependent relaxation of isolated coronary and digital arteries. Arteries from sheep with arthritis were found to have significantly attenuated responses to endothelium-dependent vasodilators. No alteration in the response to endothelium-independent dilators was observed, confirming that vascular smooth muscle function remained unaltered. This finding confirmed the utility of the ovine model to investigate the early cardiovascular changes associated with systemic inflammation. The ovine model was subsequently utilised to examine the effect of mesenchymal stem cells on endothelial cells in arthritic sheep. Mesenchymal stem cells are adult stem cells able to differentiate into cells of the mesodermal lineage. This cell population also has profound immunomodulatory capabilities which suggest therapeutic promise for a range of inflammatory and autoimmune conditions. In this study, allogeneic mesenchymal stem cells administered early in the course of arthritis development significantly improved the response of coronary and digital arteries to the endothelium-dependent dilators bradykinin and carbachol, respectively. Mesenchymal stem cell administration also reduced plasma concentrations of circulating inflammatory markers fibrinogen and serum amyloid A, and improved high density lipoprotein levels in arthritic sheep. The interactions between mesenchymal stem cells and cytokine-activated coronary artery endothelial cells were also examined in vitro to determine if mesenchymal stem cells have direct or indirect effects on endothelial cells. In direct co-culture, mesenchymal stem cells reduced the production of granulocyte-macrophage colony stimulating factor and endothelin-1 by cytokine-activated coronary artery endothelial cells. Activated monocytes cultured with mesenchymal stem cells produced less of the pro-inflammatory cytokine tumour necrosis factor- α. Additionally, and perhaps more importantly from a physiological perspective, mesenchymal stem cells were able to modulate endothelial cell function indirectly by altering the production of monocyte-derived cytokines. In summary, the work described in this thesis demonstrated that the ovine model of collagen-induced arthritis can be used to study endothelial dysfunction. These studies report for the first time that mesenchymal stem cell administration attenuates the development of endothelial dysfunction in vivo in a model of systemic inflammation. Mesenchymal stem cells were also found to be capable of modulating endothelial cell function directly and indirectly (via monocytes) in vitro. Together, these studies suggest the significant therapeutic potential of mesenchymal stem cells to modulate the early cardiovascular changes associated with systemic inflammatory diseases. Mesenchymal stem cells may therefore provide a novel therapy able to address the excess cardiovascular risk in patients suffering from systemic inflammatory conditions such as rheumatoid arthritis.