**2. The many faces of SMCs in vascular disease**

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

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

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

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‐

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

statins) reduce the onset of acute complications of atherosclerosis.

functions of vascular SMCs.

234 Muscle Cell and Tissue

inflammatory disorder [1, 4, 8].

phage-like cells [20-25].

vascular diseases.

SMCs exerts various functions during development, in normal homeostasis in adults, and in the pathogenesis of vascular diseases [2]. While vascular tissues develop, SMC need to migrate, and produce selected proteins that contribute to these functions. After birth, SMC are highly specialized in contraction, which is their main role in normal homeostasis for regulation of vessel tone and diameter to control of blood pressure and flow. Adult SMCs thus express specific contractile proteins, ion channels, and signaling molecules that are unique to this muscle compared with other muscles, including the skeletal muscle and cardiac muscle [2, 3]. Such SMC-selective or -specific genes thus serve as markers of SMCs. These include the proteins that comprise the contractile apparatus including SM α-actin, SM myosin heavy chain (SM-MHC) isoforms SM1 and SM2, h1-calponin, SM22α, and smoothelin [3]. However, some of these SMC markers are expressed, at least transiently, in other cell types during develop‐ ment, tissue repair, or disease states, while SM-MHC isoforms are specific to SMCs [2]. Therefore, SM-MHC isoforms are the most definitive markers for SMC.

Accumulation of SMC in the subendothelial space contributes to the formation of the intima, as a precursor of the future atherosclerotic plaques. The process appears to involve migration and proliferation of activated SMCs. Where those SMCs originate from is an interesting question that we discuss later. The ability of SMC to migrate and proliferate in vascular lesions often associates with their phenotypic modulation from a contractile type to a synthetic one, as characterized by loss of contractile proteins (e.g., SM-MHC) and the increased synthesis of matrix proteins (e.g., collagen) [2, 26-29]. Reduced expression of SMC-specific proteins also indicates their decreased state of differentiation. Platelet-derived growth factor (PDGF), released by platelets on the surface of dysfunctional endothelium, and activated macrophages, may participate in the loss of SMC differentiation marker genes and promote their migration and proliferation [30, 31, 32].

Collagens are major products of SMCs. The balance of collagen production by SMCs and degradation by macrophage-derived matrix metalloproteinases (MMPs) may positively or negatively contribute to the mechanisms of vascular diseases. Depending on the context, the presence of vascular SMCs within atherosclerotic plaques may be beneficial. Particularly, accumulation of fibrillar collagen in the fibrous cap of atherosclerotic plaques may be protec‐ tive. Macrophage expression of collagenases of the MMP family or reduced SMC due to cell death may impair the integrity of plaques, leading to physical disruption ("rupture") and thrombosis [5, 6, 33]. Libby et al. claimed in the early 1990s that the pro-inflammatory T cell cytokine IFNγ inhibits collagen I and III synthesis by human SMCs [34]. Interestingly, IFNγ has become known to promote pro-inflammatory macrophage activation (the so-called M1 polarization). This may indicate that a pro-inflammatory microenvironment promotes plaque instability, another example of SMC-macrophage crosstalk participating in the pathogenesis of acute cardiovascular complications. There are other examples for the beneficial or adverse role of collagen production by SMCs in vascular disease. After stent implantation, migrating SMCs cover the luminal surface of stent struts, as a healing process. But SMCs often overgrow, resulting in restenosis, which remains the most prevalent complication of percutaneous coronary intervention.
