The studies described in this thesis focus on gene therapeutic strategies to target pathological vascular wall remodeling after PT(C)A or bypass surgery. Inflammatory processes and extracellular... Show moreThe studies described in this thesis focus on gene therapeutic strategies to target pathological vascular wall remodeling after PT(C)A or bypass surgery. Inflammatory processes and extracellular proteases, both activated by mechanical and vascular injury caused by these interventions, are thought to contribute largely to the development of post-angioplasty restenosis and vein graft disease. Therefore, viral and non-viral gene therapy techniques were used in these studies to deliver genes encoding protective as well as inhibiting proteins in order to modulate the inflammatory cascade (i.e. IL-10 and the MCP-1/CCR-2 pathway) in the first part of this thesis and the plasminogen activator and MMP-system in the second part. Finally, the expression of several involving genes was blocked locally by RNA interference techniques in the last part of this thesis. The possibilities and effects of these gene therapy applications were studied in cell cultures, in a human saphenous vein organ culture model and in two mouse models of restenosis and vein graft disease. Altogether, these studies provided more insight into the pathophysiology of post-interventional remodeling and several potential therapeutic strategies were assessed. Show less
The aim of this thesis was to gain more insight in the involvement of inflammatory processes in vessel wall remodeling seen after PTA or bypass surgery and put these processes in the perspective of... Show moreThe aim of this thesis was to gain more insight in the involvement of inflammatory processes in vessel wall remodeling seen after PTA or bypass surgery and put these processes in the perspective of restenosis, vein graft failure and potential therapeutic preventive strategies. Therefore, we firstly focused on inflammation in general, using the anti-inflammatory agent Dexamethasone, assessing the effects of such a broad approach on restenosis and vein graft remodeling. Then, we further focused on some specific parts of the immune system, namely Interleukin 10 (IL10), chemokines and the complement cascade. Il10 was chosen because it is one of the most studied anti-inflammatory cytokines and this property makes it a potential candidate for ant-restenosis therapy. Furthermore, it was hypothesized that chemokines are involved in vascular remodeling, since they are generally known for their regulatory properties regarding influx of inflammatory cells to tissues and this is one of the first phenomena seen in vascular remodeling. The complement cascade was studied in this context since it contains pro-inflammatory activity and some end-products of the cascade, like chemokines, are potent chemotactic agents. Show less
