Linking Hemorrhage, Angiogenesis, Macrophages, and Iron Metabolism in Atherosclerotic Vascular Diseases

Intraplaque hemorrhage (IPH) is a phenomenon observed in advanced atherosclerotic plaques. Paterson1 was the first to propose vasa vasorum as the source of IPH. Barger et al2 described an abundance of plaque microvessels found in diseased coronary arteries compared with healthy ones and proposed that plaque neovascularization plays an important role in the pathogenesis of atherosclerosis. A postmortem study from our group established a critical relationship between erythrocyte extravasation in coronary atherosclerotic plaques (measured by the red blood cell membrane sialoglycoprotein glycophorin A) and necrotic core enlargement and plaque progression.3 In a different postmortem study, plaque macrophages were found to be 2- to 4-fold more abundant in patients with symptomatic cardiovascular disease, and the adjacent microvessel network was found to be denser.4 Kockx et al5 showed that perivascular foam cells in areas of high microvascular density within carotid plaques frequently contained platelets and erythrocytes. Phagocytosis of red blood cells was shown to be a trigger for macrophage activation in both in vitro and in vivo. It was also shown that macrophages were particularly abundant around newly formed leaky microvessels.5–7 This and other emerging data support the notion that IPH plays a causal role in promoting plaque progression via deposition of free cholesterol from red blood cells.8–10 The effect of plaque hemorrhage translates into higher plaque burden and vulnerability, which are demonstrable in imaging modalities such as magnetic resonance imaging, intravascular ultrasound, and near infrared spectroscopy.11,12 Here, we summarize recent progress made in our understanding of the collective role of IPH, angiogenesis, macrophages, and iron metabolism in atherosclerotic plaque progression. In a recent article, Sun et al13 examined the effect of the blood pressure on carotid plaque IPH diagnosed by magnetic resonance imaging in an asymptomatic …

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