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Smooth Muscle Cell Recruitment and Remodeling During Atherogenesis in Mice

Jacob Fog Bentzon 


The present PhD thesis describes two mechanisms in the development of atherosclerosis in the apoE-/- mouse model. It is based on three papers.
In paper I, we studied the origin of SMCs in atherosclerotic plaques of apoE-/- mice. Recent studies have concluded that a substantial fraction of SMCs in atherosclerosis originate from circulating progenitor cells. We reinvestigated this hypothesis by a series of BM and vessel wall transplantations, but found that plaque SMCs in apoE-/- mice are derived entirely from the local vessel wall and not circulating smooth muscle progenitor cells.
In paper II, we extended this analysis to complicated atherosclerotic plaques. Activated platelets adhering to areas of vessel wall injury have been reported to be important for the recruitment of circulating progenitor cells. To evaluate this hypothesis in the setting of atherosclerosis, we conducted a series of transplantation experiments to define the origin of SMCs after mechanical plaque disruption and superimposed thrombosis. We found no contribution from circulating smooth muscle progenitor cells.
In paper III, we studied expansive remodeling in apoE-/- mice. Expansive remodeling of the tunica media and adventitia strongly influences the effect of atherosclerotic plaque formation on luminal narrowing, but little is known about the underlying mechanisms. We found that the left coronary sinus of the aortic root features a consistent expansive remodeling response at 6 months of age that may be suitable for future mechanistic studies. Furthermore, we found that remodeling at this site was a strictly local response of the plaque-related vessel wall.
Our combined studies showed that during atherogenesis in apoE-/- mice, the local vessel wall reacts in two ways. Cells in the local vessel wall migrate inwards to constitute the SMC population in the developing plaque without contribution from circulating cells. Coincidentally, the local vessel wall bulges outwards to preserve the lumen.