Challenging the mystique Connection. Deciphering cell-matrix interactions role in atherosclerosis and restenosis

Sammanfattning: Atherosclerosis is the underlying cause for myocardal infarction, stroke and peripheral arterial disease, collectively referred to as cardiovascular diseases. These represent the major cause of death globally. Phenotypic modulationof vascular smooth muscle cells form a contractile to a synthetic state and subsequent migration into the intima, isone of the prime events that marks the genesis of atherosclerosis. To effectuate, cells are required to weaken the connection with their own basment membrane, a network of extracellular matrix molecules. This thesis exploresthe importance of Cell-ECM connections in atherosclerotic and restenostic settings using mice as a model. In detail, this thesis discusses the role of dystrophin and beta-sarcoglycan, two important components of theDystrophin-glycoprotein complex — one important way cells use to communicate with basement membranes.In paper I & II, we investigated whether beta-sarcoglycan has a role in the development of atherosclerotic plaquesand vascular injury induced neointima formation. Much to our surprise, we found that the absence of betasarcoglycanreduced advanced atherosclerotic plaque development, and in contrast, stimulated neo-intimalhyperplasia under conditions involving the presence or absence of an ApoE-deficient background, respectively.Under an atherosclerotic setting, the relative area of differentiated smooth muscle cells in the plaques wasincreased in beta-sarcoglycan deficient mice. Further, deficiency of beta-sarcoglycan decreased the weight ofvisceral adipose tissue and reduced the size of both brown and white adipocytes.In paper III, we utilized mdx mice to determine if there is also a role for dystrophin in the process of atheroscleroticplaque development. We obtained similar results as in the study with sarcoglycan deficient mice; the mdx miceexhibited a significant attenuation of advanced atherosclerotic plaque growth with an increase in the relative areaof differentiated smooth muscle cells in their plaques. A reduction in T-cell content in these plaques and an overallreduction in systemic inflammation was also observed.In paper IV, we observed that actin dynamics influence genes important for regulation of VSMC phenotypes andfound dystrophin to be significantly increased and decreased by actin polymerization and depolymerization,respectively. A significant downregulation of dystrophin was observed under the influence of vascular injury.To summarize, this thesis uncovers the important influence of a functional CELL-ECM linkage mediated bydystrophin and beta-sarcoglycan on vascular lesion development.