The vascular response to oxidative and mechanical stress

Abstract

Atherosclerosis is a chronic inflammatory disease, which is one of leading causes of death in the Western world. The study of the vascular response to initiators of inflammation can lead us to a better understanding of the basic mechanisms that lead to the development of this disease. Balloon injured arteries develop a neointima. that is composed primarily of smooth muscle cells that have migrated from the media and proliferated. Studies in vitro have shown that oxidized LDL has proinflammtory effects on vascular cells and antioxidants have reduced atherosclerosis in experimental animal models. An experimental model was developed to study the local oxidation of LDL in vivo in the arterial wall. LDL (6mg/kg) was injected intraperitoneally or intravenously into male Sprague Dawley rats. The uptake and modification of the LDL was studied immunohistochemically. These studies suggested that LDL first enters the arterial wall and becomes oxidized. Immunohistochemical staining for the active form of the redox sensitive transcription factor, NF-[kappa]B, was seen after the presence of oxLDL suggesting that NF-[kappa]B activation was due to the oxidation of LDL. NF-[kappa]B activation was also associated with the adhesion molecule ICAM-1 in the endothelium. The mechanisms behind LDL modification in vivo and in vitro was investigated and it was found that modification of LDL involved both enzymatic and radical-initiated mechanisms. Smooth muscle phenotypic modulation, proliferation, and synthesis of extracellular matrix as well as intracellular (macrophage and smooth muscle) lipoprotein uptake and lipid accumulation are key events in the development of the atherosclerotic plaque. From in vitro and in vivo studies, we found that contractile cells have the ability to take up cholesterol and distribute it to the plasma membrane or expel it from the cell. In synthetic smooth muscle cells, however, cholesterol is esterified and retained in the cell. Immunization against oxLDL in hypercholesteremic rabbits decreased the neointima formation after balloon injury in rabbits. Although a humoral response was mounted in these animals it did not seem to be the cause of the protective effect of immunization. The protective effect may be due to cell-mediated immunity but this needs to be studied further. An in vitro injury model for smooth muscle cells was developed. With this model it was shown that smooth muscle cells themselves release factors after injury that contribute to their growth. The growth factor bFGF was shown to be released after injury that induced a PDGF AA intracrine loop, which in turn activated DNA synthesis. Collectively, the results presented in this thesis confirm and extend the role of the inflammatory process in the vascular response to oxidative and mechanical stress.