The Role of Type VIII Collagen in Fibrous Cap Formation and Progression of Atherosclerosis
Collagens play an integral role in the progression of atherosclerosis. Collagen synthesis and remodelling influence inflammation, smooth muscle cell (SMC) proliferation and migration, and properties such as plaque tensile strength and mechanical stability. Type VIII collagen is expressed at low levels in the arterial system however, it is dramatically up-regulated in atherosclerosis. The purpose of this thesis is to determine the role of type VIII collagen in the development of atherosclerosis. Our first study uses Col8+/+;Apoe-/- and Col8-/-;Apoe-/- mice on an atherogenic diet to illustrate that type VIII collagen plays a role in formation of the fibrous cap. Deletion of type VIII collagen resulted in reduced SMC and fibrillar type I collagen content and gelatinase activity. Reduced fibrous cap thickness and increased necrotic core size were observed in plaques from these mice. The second study shows that the advanced plaques from mice deficient in type VIII collagen have increased macrophage proliferation and accumulation. Increased features iii associated with plaque instability such as breaks in the elastic lamina and cleaved collagen content were also observed. Plaque stiffness was reduced in Col8-/-;Apoe-/- mice, suggesting that type VIII collagen plays a role in the mechanical integrity of the plaque. In the third study, we use a bone marrow transplantation model to generate chimeric mice with myeloid-specific deletion of type VIII collagen (Col8-/-ď +/+). We show that plaques from Col8-/-ď +/+ mice have reduced elastin content compared to control mice. Finally, preliminary work suggests a role for type VIII collagen in the expression of fibrillar collagens. Plaques from Col8-/-;Apoe-/- mice show reduction of type I and III collagen accumulation and a reduction in type III collagen expression is observed in SMCs from Col8-/- mice. In summary, the studies presented here suggest that type VIII collagen confers increased plaque stability by promoting SMC infiltration and fibrosis as well as reducing inflammation. This work underscores the
Atherosclerosis, Cell biology, Collagen, Matrix remodelling, Type VIII collagen
Networked Digital Library of Theses and Dissertations