The atherosclerotic plaque formation process in the arterial walls is a very complex process. Plaque development occurs due to an interplay between endothelial cells, smooth muscle cells, and immune cells. There is an increase in endothelial permeability and activation of signaling molecules, including inflammatory mediators and cell adhesion molecules. Moreover, circulating lipoproteins (particularly low-density lipoproteins – LDL) can cross the endothelial layer and be deposited in the intimal space, where they undergo oxidative changes (oxLDL), increasing the local inflammatory response. Furthermore, monocytes mature into macrophages, being recruited via attractant chemokines, and while they attempt to clear oxLDL via phagocytosis, they are converted into foam cells and ultimately undergo necrosis. In addition, vascular smooth muscle cells (VSMCs) proliferate and migrate from the media to the intima, leading to intimal hyperplasia, and these cells organize and deposit extracellular matrix, forming a fibrous cap. Erosion or rupture of the fibrous cap will lead to thrombotic occlusion or distal embolism, resulting in ischemia.

In this process, matrix metalloproteinases (MMPs) play an important role. MMPs are a family of zinc-dependent endoproteases that are secreted by endothelial cells, VSMCs, fibroblasts, osteoblasts, macrophages, neutrophils, and lymphocytes. During stable atherosclerotic plaque development, MMP-2 cleaves the endogenous nitric oxide synthase, causing endothelial dysfunction and facilitating infiltration of LDL into the intima. Then, MMP-2 expressed by activated platelets promotes monocyte transmigration into the intima . MMP-2 also facilitates oxLDL-induced VSMCs migration to the intima, forming the fibrous cap. Therefore, it can induce migration and proliferation of VSMCs, enhancing plaque stability. However, MMP-2 levels are higher in unstable than in stable atherosclerotic plaque, indicating that MMP-2 plays a role in plaque vulnerability and propensity to rupture. They participate in the degradation of the extracellular matrix (ECM), which will cause thinning of the plaque fibrous cap, becoming more prone to rupture.

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