Fibromodulin and Dystrophin in Atherosclerosis: Novel roles for extracellular matrix in plaque development

Sammanfattning: Cardiovascular disease represents nearly half the cases of noncommunicable diseases worldwide and is the leading global cause of death. The main underlying cause is atherosclerosis, and in atherosclerotic plaque progression the structure, composition and integrity of a dynamic extracellular matrix (ECM) is one very important factor. This thesis discusses the importance of the connection between the ECM and cells for atherosclerotic lesion development. It also tests the hypothesis that changes in this connection – whether through a modified collagenous ECM, or modification in a cellular protein directly linking cells to ECM components – have a significant impact on atherosclerotic plaque structure and stability.

Fibromodulin is a small leucine-rich repeat proteoglycan of the ECM involved in the regulation of collagen fiber synthesis. In the fibrous murine atherosclerotic plaque, we found collagen fibrils synthesized in the absence of fibromodulin to be thicker and more heterogeneous, compared to fibrils generated in the control mouse. Murine plaques with an inflammatory phenotype, with a fibromodulin-deficient ECM, were also smaller with decreased lipid accumulation, whereas cell proliferation was increased. In addition, we show, for the first time, that high fibromodulin expression in the most stenotic region of a human carotid artery plaque is found in plaques from symptomatic patients, and in patients with diabetes. Fibromodulin expressed in human plaques co-localize with Oil Red O-staining and correlates with the area stained for lipids (quantified as percentage). Fibromodulin also correlates with the pro-inflammatory cytokines MIP-1β and sCD40L, as well as with VEGF and inversely with the anti-inflammatory cytokine IL-10.

Dystrophin, and the dystrophin-glycoprotein complex (DGC), link the actin cytoskeleton to the basement membrane. This thesis provides novel data on dystrophin deficiency, as illustrated by the mdx mouse. The absence of dystrophin stimulates neointimal hyperplasia, but inhibits atherosclerotic lesion development driven by lipid-retention. In the mdx-mouse, laminin expression is decreased in the endothelium of atherosclerotic lesions with an inflammatory phenotype, suggesting that altered endothelial cell function and an abnormal basement membrane may be a possible explanation for the attenuated plaque development.

In summary, this thesis shows that collagen structure and remodeling affects the growth, development and composition of atherosclerotic lesions, on the one hand promoting mechanical stability, and on the other hand affecting lipid accumulation and inflammation. In addition, growth of vascular lesions can be inhibited or promoted by a functional connection between cells and the ECM mediated by dystrophin and the DGC.