**1. Introduction**

Atherosclerosis is a complex multifactorial disorder and involves various cell types, including vascular smooth muscle cells (SMCs), macrophages, lymphocytes, neutrophils, and endothe‐ lial cells [1]. Evidence has established that each cell type changes its phenotype in response to a microenvironmental cue. SMC phenotype ranges from the undifferentiated state to differ‐ entiated state during vascular development [2]. Vascular lesions in adults also exhibit such

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phenotypic diversity of SMCs, which often mirrors their functions (e.g., contractile vs. synthetic SMCs). The role of lesional SMCs appears to vary depending on the disease context and stage of the disease. The production of extracellular matrix by SMCs often contributes to the lesion development [3, 4], but also may exert beneficial effects (e.g., stabilizing the fibrous cap of atherosclerotic plaques) [5, 6]. SMCs often reside in vascular lesions in close proximity to macrophage clusters, and appear to be influenced by factors released from inflammatory cells. Particularly, macrophages in the lesion may promote activation and pro-atherogenic functions of vascular SMCs.

In the middle of the nineteenth century, German pathologist Rudolf Virchow made significant contributions to cardiovascular medicine. He identified the formation of tunica intima as a key atherosclerotic change and suggested that the contents of the intima promote expansion of matrix components [4, 7]. He further indicated that infiltrated leukocytes may contribute to the pathogenesis of atherosclerosis. Numerous studies have subsequently unraveled the role of immune cells, leading to a widely accepted theory that atherosclerosis is a complex chronic inflammatory disorder [1, 4, 8].

Coronary and cerebrovascular atherosclerosis underlies life-threatening complications such as acute myocardial infarction and stroke. Major risk factors, including dyslipidemia, acceler‐ ate the development of atherosclerotic changes in arteries. Elevated levels of low-density lipoprotein (LDL) cholesterol in the circulating blood cause dysfunction of endothelial barriers and infiltration of circulating leukocytes (e.g., monocytes) into the artery wall. Monocytes differentiate into macrophages within the subendothelial space. Accumulating LDL under‐ goes oxidative modifications in the arterial wall (oxidized LDL), which is then recognized and taken up by macrophages, leading to the accumulation of lipid-laden foam cells. Foam cells secrete proinflammatory mediators that facilitate lipoprotein retention and maintain vascular inflammation [9, 10]. To minimize the risk of atherosclerotic complications, primary and secondary prevention strategies seek to control risk factors such as hyperlipidemia. LDLlowering drugs (e.g., 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors or statins) reduce the onset of acute complications of atherosclerosis.

Bone marrow-derived progenitor cells, including endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs), also may serve as a source of atherosclerosis-related cell lineages [11, 12]. Pioneering work suggested that these progenitors differentiate into mature and functional endothelial cells (ECs) and SMCs, respectively, in physiological and pathological settings [11, 13]. However, their functional contributions to atherogenesis remain unclear [14-17]. The evidence also indicated that some intimal SMC may originate from circulating monocytes or their subset [14, 18, 19]. In contrast, other lines of evidence have proposed an opposite direction of transdifferentiation of SMC into macrophage or macro‐ phage-like cells [20-25].

In this chapter, we address the functions and interplay of SMCs and monocytes/macrophages present within the pathological arterial wall. We also discuss emerging concepts of the interchangeability of these two cell lineages. Better understanding of these complex biologies may provide important insight into the mechanisms and new therapeutic strategies for vascular diseases.
