Atherosclerosis and arterial remodeling Atherosclerosis is a chronic inflammatory disease and the primary cause of cardiovascular events like myocardial infarction. Based on plaque composition, stable and unstable atherosclerotic lesions are discriminated. Unstable lesions are prone to rupture and subsequent thrombus formation often results in acute occlusion of the artery. The size of the lumen of an atherosclerotic artery is determined by the atherosclerotic lesion, together with arterial remodeling. In early stages of atherosclerosis, outward arterial remodeling compensates for lumen loss due to plaque formation. However, in advanced atherosclerotic lesions, outward arterial remodeling is associated with rupture prone lesions. Inflammation and immune responses are involved in the initiation and progression of atherosclerotic disease. The immune system responds effectively to harmful agents by close interplay between the innate and adaptive immune systems. The innate immune response is the first line of defense against invading pathogens. Immune cells recognize pathogens via pattern recognition receptors, including scavenger receptors and Toll-like receptors. B- and T- cells are involved in the highly specific adaptive immune response. Toll-like receptors Toll-like receptors are not only expressed by immune cells, but also by vascular cells. In healthy arteries TLR4 is expressed in low levels. In atherosclerotic lesions, however, TLR4 expression is markedly increased. TLR4 is involved in intima formation and vulnerability for the development of carotid atherosclerosis. Whether TLR4 is also involved in arterial remodeling, the other determinant of lumen loss is investigated in this thesis. The Toll-like receptor 4 signaling in arterial remodeling We demonstrated that TLR4 is involved in outward arterial remodeling both with and without intima formation. TLR4 expression is upregulated during outward remodeling. TLR activation results in translocation of NF-?B into the nucleus and transcription of inflammatory genes. Downstream of TLR4, we investigated the role of NF-?B p50 in arterial remodeling. The p50 subunit is known as a regulatory subunit of NF-?B signaling. In our study, targeted deletion of the regulatory NF-?B p50 subunit enhanced flow-induced outward arterial remodeling. During outward arterial remodeling, levels of endogenous TLR4 ligands EDA and HSP60 are increased. Extra Domain A is incorporated in fibronectin during embryogenesis, wound healing, cellular damage and atherogenesis. We demonstrated a role of EDA in the process of outward remodeling, probably due to the diminished migration capacity of cells without EDA. Endogenous Toll-like receptor 4 ligand EDA in atherosclerosis Higher EDA levels are detected stable human atherosclerotic plaques. This observation implies that the detection of an endogenous TLR4 ligand not necessarily represent an inflammatory environment destabilizing the vulnerable plaque, but also may trigger the stabilization of atherosclerotic lesions. Interaction between Toll-like receptor 4 and Transforming Growth Factor ? signaling We found an association of endogenous TLR4 ligand EDA with Endoglin, an accessory receptor of TGF? in atherosclerotic lesions. This suggests communication between TLR4 and TGF pathways in atherosclerotic lesions. In monocytes, several sets of mRNAs are regulated by both TLR4 and TGF? stimulation and these mRNAs may play an important role in the progression of atherosclerotic disease leading to clinical events
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