EPCs are involved in physiological and pathological angiogenesis, as they are actively recruited at sites of new vessel growth. Moreover, circulating EPCs contribute to endothelial regeneration and vascular repair. Several lines of evidence indicate that EPCs also play a role in adult neovascularization, as well as in the maintenance of endothelial integrity and function.
EPCs normally circulate in peripheral blood and replace injured endothelial cells for vessel repair. Cerebrovascular disease and cardiovascular and peripheral atherosclerosis, have been associated with lower numbers of circulating EPCs. In addition, low EPC levels have been shown to represent an independent risk factor for future cardiovascular events. Although the charac- teristics of EPCs have been studied in various vascular diseases, there are only a few studies on the role of these cells in patients with MMD [7, 23] .
Endothelial Cells
The endothelium regulates vascular homeostasis and is responsible for angiogenesis, which is a process mediated by the sprouting of endothelial cells from pre-existing vessels. The proliferation and migration of endothelial cells in response to molecular signals are major components of newly formed vessels in adults [1] . Endothelial cells are heterogeneous in morphology, function, and gene expression profiles. Physically, endothelial cells have been shown to differ in size and thick- ness. The most important characteristic that differentiates these cells is the integrity of the tight junctions. The blood–brain barrier, composed of continuous endothelial cell tight junctions, is an important protective factor for the CNS. The tight junctions are modulated by factors that include VEGF. Mitotically, the endothelial cells in the brain are tightly downregulated. Hence, they are upregulated during angiogenesis [24] . Some studies suggest that endothelial cells play an impor- tant role in the initiation of angiogenesis, whereas other studies suggest that these cells are induced to replicate and migrate to complete the angiogenic process [24] . A practical relationship between endothelial cells and MMD angiogenesis has not been described.
80 J.H. Kim et al.
Mural Cells: Pericytes and Smooth Muscle Cells
The vascular tube must be stabilized by mural cells. The recruitment of mural cells (i.e., pericytes and SMCs) of blood vessels is an important step of vessel maturation [25] . The initial step of maturation is the fusion of the newly formed capillaries with other vessels. The process of vessel maturation includes a step-by-step transition from the growing vessel bed to the quiescent, fully formed, and functional network. Therefore, the recruitment of pericytes and accumulation of ECM proteins in the adjacent basement membrane contributes to vessel maturation and to its transition to the quiescent state. To achieve this, mesenchymal cells in the surrounding tissue proliferate and migrate to the abluminal surface of the premature vessels. These mesenchymal cells subsequently differentiate either into pericytes, located within the basement membrane, or into vascular SMCs, found abluminally of the basement membrane. Pericytes are in direct intercellular contact with endothelial cells and form the walls of capillaries and immature blood vessels, whereas the walls of mature blood vessels and those of large-diameter vessels (i.e., arteries and veins) are formed by several layers of SMCs separated from the endothelium by a layer of basement membrane [26] . SMCs derived from the STAs of MMD patients, together with PDGF, are actually involved in intimal thickening [10] . In MMD SMCs, PDGF-AA and -BB stimulate cell migration but not DNA synthesis.
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Introduction
Immunological phenomena have pervasive effects on the human body. Many physiological and pathological processes involve the immune system. Because of this pervasiveness, it is often difficult to know whether an observed immunological reaction truly underlies a process or whether it is simply an epiphenomenon. The role of the immune system in moyamoya disease is a controversial issue. The etiology of moyamoya disease is currently unknown. Various etiologies, genetic and environmental, have been proposed; however, none have been definitively proven. There is a lot of evidence for immunological abnormalities in patients with moyamoya disease. However, much of the evidence is indirect and lacks a solid causal relationship.
Nonetheless, it is strongly believed that immunological processes play an important role at least in the progression of moyamoya disease. In this chapter, the pathological and epidemiological evidence that supports the immunological origin of moyamoya disease is discussed.