Vein graft surgery to treat occlusive arterial disease is a common applied procedure. Each year more than two million vein graft surgeries are performed worldwide. The major drawback of vein... Show moreVein graft surgery to treat occlusive arterial disease is a common applied procedure. Each year more than two million vein graft surgeries are performed worldwide. The major drawback of vein grafting is that within 10 years after vein graft surgery 50-60 % of the vein grafts suffer from patency loss due to thrombosis, intimal hyperplasia formation, accelerated atherosclerosis and rupture. Endogenous factors orchestrate the development and failure of vein grafts. Investigating the role of endogenous constituents on vein graft remodeling can enhance our basic knowledge of the involvement of these factors in vein graft remodeling. By interfering in the function of endogenous factors, as we showed in this thesis, vein graft remodeling can be negatively or positively influenced depending on the factor and strategy used. New therapeutic strategies can be developed based on this knowledge. In this thesis we investigate the role of innate immune components, complement system factors, toll like receptors, mast cells and NK cells and the role of Annexin A5 in vein graft remodeling. Furthermore we explored the role of plaque stability, plaque neovascularization and extracellular matrix remodeling in a hypercholersterolemic mouse vein graft model. Show less
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
