2 with AT1 receptor enhances erythroid diﬀerentiation in the BM [20]. Ang II-stimulated erythroid progenitors formed signiﬁcantly higher numbers of burst forming unit-erythroid (BFU-E) colonies in normal human erythropoiesis. Recently, Fukuda and Sata [21] proposed a hypothesis that the local RAS in BM plays crucial roles in atherosclerosis. They have demonstrated that Ang II-AT1R pathway in BM contributes to atherosclerotic development in the hypercholesterolemic mice. The aim of this paper is to outline the function of local BM RAS during the course of progression and destabilization of atherosclerosis. 2. RAS Activation in Atherosclerotic Lesions 2.1. Potential Eﬀects of Activated RAS on Vascular Structure. Atherosclerosis is a chronic inﬂammatory disease involving accumulation of lipoproteins and mononuclear cells in the subendothelial space with a result of a cascade of events in blood vessels leading to a remodeling of the arterial wall and a consecutive reduction in lumen size. Novel advances in biotechnology and molecular methods have enabled us to understand the molecular pathways that induce and promote inﬂammatory responses in the formation of atherosclerotic lesions. Although RAS plays a central role in the control of blood pressure, ﬂuid volume, and sodium balance, overactivity of this system contributes to the pathogenesis of atherosclerosis by simulating a series of coordinated cellular and molecular events observed in the lesions [22–25]. In the past Ang II was believed to aﬀect atherosclerosis through its hemodynamic eﬀects, but in the last two decade it has been shown that, direct cellular eﬀects of Ang II aﬀect the structural changes in the vessel wall seen in atherosclerosis [26]. All components of the RAS are expressed in the vessel wall and mostly the eﬀects of Ang II are mediated by the G-protein-coupled receptors AT1 and AT2 [27]. Both AT1R and AT2R have been well identiﬁed in the vessel wall; AT1R is believed to mediate most of the atherogenic actions of Ang II [28, 29]. Yang et al. [30] demonstrated that in hypercholesterolemic atherosclerosis in rabbits, the density of AT1 receptors in the media of diseased blood vessels is increased ﬁvefold compared to healthy animals. They also found a signiﬁcant AT1R binding in the neointima of the diseased arteries. The highest receptor density in the vessel wall is on vascular smooth muscle cells (VSMCs), but cell culture studies also established a signiﬁcant AT1R-mediated responses in endothelial cells and macrophages and AT2Rs comprise only about 10% of total angiotensin receptors in healthy blood vessels [30, 31]. Those results suggested that not only systemic but also local Ang II-AT1R pathway could contribute to initiation and progression of atherosclerosis in blood vessels. 2.2. Eﬀects of Activated RAS on Vascular Endothelial Cells. Ang II, produced locally by endothelial ACE, is one of the key substances that aﬀects endothelial function (or dysfunction). To better understand the eﬀect of Ang II on vascular pathobiology, one must need to examine the pivotal role of the endothelium in maintaining normal vascular Cardiology Research and Practice function and structure. Ang II is synthesized by and has a key action on the endothelium: it exerts direct inﬂuence on endothelial function [7, 32]. Vascular endothelium is known as a metabolically active secretory tissue, presents a thromboresistant surface to blood, and acts as a selective macromolecular barrier. It is now believed that structural abnormalities and function of endothelial cells is the cause of not only vascular diseases including atherosclerosis but also certain visceral disorders [33]. Endothelial cells produce factors that regulate vessel tone, coagulation, cell growth and death, and leukocyte migration. Under the control of the endothelium and other factors, VSMCs are also able to release cytokines and growth-regulatory factors that can inﬂuence vascular cellular phenotype and growth [7, 34]. Cytokines can exert both pro- and antiatherogenic actions because they are multipotent mediators of inﬂammation and immunity that can aﬀect key functions of vascular wall cells. The functions of vascular wall cells regulated by cytokines may inﬂuence lesion initiation, progression, or complication. The cytokines also adjust endothelial functions that control the development and stability of blood thrombi. Thus, cytokines can inﬂuence multiple aspects of atherogenesis and provide new and interesting targets for therapeutic management [35]. Endothelial cells also regulate vascular tone in a strict balance between vasodilators-like nitric oxide (NO), and vasoconstrictors-like Ang II. This balance is crucial to a healthy endothelium. When Ang II is elevated, endothelial dysfunction begins. The imbalance toward Ang II by itself can cause many of the changes in the endothelium that set the atherosclerotic process in motion [36]. Ang-II upregulates expression of adhesion molecules, cytokines, and chemokines and exerts a proinﬂammatory eﬀect on leucocytes, endothelial cells, and VSMCs [22, 24, 26, 37–39]. And also Ang II upregulates expression of vascular endothelial growth factor (VEGF) which con- tributes to adventitial angiogenesis [40–42]. Acting via the type 1 receptor, Ang II initiates an inﬂammatory cascade of reduced nicotinamide-adenine dinucleotide phosphate oxidase, reactive oxygen species (ROS), and nuclear factor- kappa B, which mediates transcription and gene expression and increases chemokines and adhesion molecules [43]. The Ang II type 1a (AT1a) receptor is expressed on multiple cell types in atherosclerotic lesions, including bone- marrow-derived cells and vascular wall cells, and mediates inﬂammatory and proliferative responses. Indeed, Ang II infusion accelerates atherogenesis in hyperlipidemic mice by recruiting monocytes and by activating vascular wall cells [44]. In advanced atherosclerotic lesions, Ang II stim- ulates matrix metalloproteinases (MMPs) and plasminogen activator inhibitor-1 expression, causing destabilization of atherosclerotic plaque and alteration of ﬁbrinolytic balance [45–47]. Besides inducing oxidative stress, endothelial damage, and disease pathology including vasoconstriction, thrombo- sis, and inﬂammation, Ang II is also involved in vascular remodeling, acting as a bifunctional growth factor that stim- ulates production of growth factors and vasoactive agents (e.g., platelet-derived growth factor, insulin-like growth factor, and basic ﬁbroblast growth factor) in VSMCs [48, 49].