The Role of M2 Macrophage Subset and Fibrocytes in Mouse Models of Atherosclerosis and Angioplasty-restenosis

Neointimal proliferation is a feature of several vascular pathologies, including atherosclerosis and restenosis post-angioplasty. Atherosclerosis is characterised by the formation of plaques, which is composed of a lipid core and a fibrous cap. Pivotal cells in plaque formation are monocytes and macrophages, which are traditionally known for their ability to engulf excess lipids to become foam cells, a component of the lipid core. Fribrocytes, which are a type of cell sharing similar characteristics to a subset of macrophages, have also been shown to contribute towards plaque formation. The principal cells identified in the fibrous cap are vascular smooth muscle cells or smooth muscle-like cells. The potential of a plaque to rupture is determined by its stability, which in turn depends on the ratio of the lipid core to fibrous cap. The rupture of a plaque ultimately leads to myocardial infarctions and strokes, often resulting in death. One surgical intervention is the use of balloon angioplasty with or without stents, which increases the patency of the obstructed lumens. However, a major disadvantage of this method is intimal hyperplasia (IH) that occurs as a response to endothelial injury, subsequently leading to restenosis of the arterial lumen. The pathophysiology of IH is similar to that of atherosclerosis, although it is known to occur on a more accelerated time frame. However, over the past two decades, the plasticity of monocytes has been widely reported in the literature. The ability of monocytes to polarise into a pro-inflammatory M1 phenotype or an anti-inflammatory M2 phenotype, depending on the environment, has been noted. Furthermore, the similarities between M2 macrophages and fibrocytes in their functionality and marker expression have also suggested a relationship between these cells. Therefore, the roles of M2 macrophages and fibrocytes in atherosclerosis and IH, and the effects of a high fat diet, which is one of the major risk factors in vascular disease, were investigated. The results from a mouse model of acute arterial injury, which represents an IH model, revealed that while the presence of a high fat diet did not significantly affect the percentage intimal area over a 4 week period, it nevertheless delayed the cellular events associated with a normal healing process. This was characterised by the persistence in the numbers of macrophages, while a delay was noted in the anti-inflammatory M2 macrophage subset and fibrocytes to the site of injury. Similarly, using an apoE knockout mouse model of atherosclerosis, results showed that the presence of a high fat diet not only significantly reduced the number of fibrocytes, but also accelerated the formation and complexity of the atherosclerotic plaque. The relationship between M2 macrophages and fibrocytes was also determined using an adoptive transfer model, where donor monocytes were labelled and injected into recipient mice that had undergone acute arterial injury. Results of this study showed that fibrocytes are derived from monocytes via the M2 macrophage population. Additionally, a large proportion of these circulating fibrocytes played a substantial role in neointimal proliferation. Together, these studies have shown that fat inhibits M2 macrophages and fibrocytes from playing a significant role in atherosclerosis and restenosis post-angioplasty, possibly polarising the macrophages towards the pro-inflammatory M1 phenotype. These results further support the role of statins and PPAR agonists in modulating the effects of high cholesterol levels. In addition, determination of the fibrocyte lineage also enables us to establish the crucial factors which control their development from monocytes, thus allowing us to modulate the cellular pathway towards one that is beneficial in wound healing and tissue repair. Consequently, this may have a significant impact on the morbidity and mortality associated with unstable atherosclerotic plaques and the increased rates of restenosis post-angioplasty