Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non–foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163⁺ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1α and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163⁺ macrophages. Within these cells, activation of HIF1α via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163⁺ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1α/VEGF-A pathway.

Iron is fundamental for life-essential processes. However, it can also cause oxidative damage, which is thought to trigger numerous pathologies, including cardiovascular diseases. The role of iron in the pathogenesis of atherosclerosis is still not completely understood. Macrophages are both key players in the handling of iron throughout the body and in the onset, progression and destabilization of atherosclerotic plaques. Iron itself might impact atherosclerosis through its effects on macrophages. However, while targeting iron metabolism within macrophages may have some beneficial effects on preventing atherosclerotic plaque progression there may also be negative consequences. Thus, the prevailing view of iron being capable of accelerating the progression of coronary disease through lipid peroxidation may not fully take into account the multi-faceted role of iron in pathogenesis of atherosclerosis. In this review, we will summarize the current understanding of iron metabolism in the context of the complex interplay between iron, inflammation, and atherosclerosis.