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Miura et al. Vessel Plus 2019;3:1 I http://dx.doi.org/10.20517/2574-1209.2018.69 Page 3 of 15

Figure 1. Formation of atherosclerosis. Atherosclerosis begins at the sites of EC damage or dysfunction, and develops with inflammatory
reactions and dynamic interactions among plasma molecules including LDL and Ox-LDL, monocytes and macrophages. EC: endothelial
cell; LDL: low density lipoprotein; Ox-LDL: oxidized LDL; CAM: cell adhesion molecule; ROS: reactive oxygen species; SMC: smooth
muscle cell

ECM degradation by matrix metalloproteinases (MMPs) are promoted and associated with more necrotic
environment within atherosclerotic plaques. As a result, atherosclerotic lesions are furthermore developed
and matured.

CA PLAQUE VULNERABILITY
An atherosclerotic CA plaque consists of a lipid core with inflammatory cell infiltrations and a fibrous cap,
and is classified into stable and unstable or vulnerable ones. A stable plaque is characterized by a thicker
fibrous cap, which prevents plaques from rupture. In contrast, the characteristics of unstable or vulnerable
plaque is intra-plaque hemorrhage and a large lipid core covered with a thin fibrous cap, which contains
less ECM and SMCs, and is often associated with the infiltration of inflammatory cells and the secretion
[25]
of MMPs and cytokines . Several reports have shown that a rich network of small vessels, that is, vasa
[26]

vasorum,is interweaved into the ECM of most of mature plaques . Unstable or vulnerable plaque is more
likely to rupture, causing thromboembolic strokes. Intra-plaque hemorrhage is also known as a predictor for
thromboembolic strokes and the recurrence. As well, strong correlations are observed between intra-plaque
hemorrhage and plaque rupture, and symptomatic CA stenosis was more frequently associated with intra-
plaque hemorrhage compared with asymptomatic CA stenosis (74% vs. 32%) .
[27]

[28]
Many atherosclerotic mediators play a role in CA plaque vulnerability [28-30] . Morgan et al. reported the
relationships between MMPs-1 or -12 and CA plaque instability: MMP-1 was upregulated more in a CA
plaque with a thin fibrous cap compared with that with a thick fibrous cap, and MMP-12 was induced
[29]
more in a ruptured CA plaque than a CA plaque with no disruption of a fibrous cap. Montecucco et al.
demonstrated that the down-regulation of cannabinoid receptor type 2 that prevents neutrophil release
of MMP-9 caused an increase in vulnerability in a symptomatic CA plaque. It was also found that anti-
apolipoprotein (Apo) A-1 auto-antibodies played a role in an increase in histological features of plaque
[30]
[29]
vulnerability in severe CA stenosis . More recently, Rao et al. revealed that triggering receptor expressed
on myeloid cells (TREM)-1 related to MMPs-1 and -9 was increased in a symptomatic CA plaque, suggesting
a potential role of TREM-1 in CA plaque destabilization.