Role of Hemoglobin-Stimulated Macrophages and Intraplaque Hemorrhage in the Development of Vascular Diseases

Intraplaque hemorrhage plays a critical role in the life of advancing atherosclerotic plaques, not only by triggering an acute increase in lesion size but also by attracting macrophages to the site. Lysis of erythrocytes in these areas is thought to be caused by oxidative stress, which induces the release of free Hb (hemoglobin), which is quickly bound by haptoglobin to form Hb-haptoglobin complexes. Macrophages are the only cells in the body capable of scavenging these complexes through the CD (cluster of differentiation) 163 scavenger receptor, which mediates Hb-haptoglobin ingestion, driving their differentiation. Emerging data suggest that these Hb-stimulated macrophages play an essential role in responding to intraplaque hemorrhage through mediating iron metabolism and influencing other cell types, including endothelial and smooth muscle cells. This review focuses on the role of Hb-stimulated macrophages in promoting atherogenesis through their effects on (1) endothelial activation, neoangiogenesis, and vascular permeability; (2) endothelial-to-mesenchymal cell transition and subsequent apoptosis; and (3) the prevention of smooth muscle cell osteogenic transformation and calcification. These functions may also be relevant to other vascular diseases where erythrocyte accumulation drives the formation of Hb-stimulated macrophages, which is a fundamental response to hemorrhage no matter the clinical setting.