**1. Introduction**

The cell composition of the human arterial intima has been intensely studied but is still not well understood [1]. The majority of cell population in normal and atherosclerotic intima is represented by cells expressing α-actins, which are thought to be smooth muscle cells [2]. According to the current paradigm, smooth muscle cells show striking plasticity responding to microenvironment signals and thus can be presented by different phenotypes [3-7]. Immune-inflammatory cells also reside in the intima of healthy arterial walls [8]. Resident immune-inflammatory cells (macrophages, lymphocytes, and dendritic cells) represent only a minority of the subendothelial cell population, but their proportion increases during the development of atherosclerotic lesions, reaching up to 20% of the total cell content [9].

Some antigens, which are absent in medial smooth muscle cells, were detected in intimal smooth muscle cells [10-13]. In particular, using 3G5 antipericyte antibody, presence of stellateshaped pericyte-like resident cells in normal and atherosclerotic human aortic intima has been found [10, 11]. In all analyzed aortic tissue specimens, 3G5+cells were found to account for more than 30% of the total intimal cell population of undiseased intima. In the atherosclerotic lesions, the number of 3G5+ cells becomes notably lower than that in undiseased intima [11]. The use of 2A7 antibody that identifies "activated" pericytes revealed the presence of 2A7+ cells in atherosclerotic plaques, while no 2A7+ cells were detected in normal intima [12]. The strongest correlation was established between the number of pericyte-like cells and the content of intimal lipids [12]. The correlation coefficients between the number of pericyte-like cells and collagen content and intimal thickness were greater than the correlation coefficients for smooth muscle cells. On the basis of these findings, pericyte-like cells but not smooth muscle cells or other cell types have been declared to be the key cellular element driving the formation of atherosclerotic lesions [14].

The present chapter aims to detail the abovementioned issues. The present chapter also aims to promote a view that α-smooth muscle actin+ pericyte-like cells represent the key players in the development of atherosclerotic lesions.

### **2. Structural organization of human aortic intima**

The wall of large arteries consists of three layers, namely, the tunica intima, the tunica media, and the tunica adventitia. Furthermore, the tunica intima of the adult human aorta consists itself of two layers separated by distinct boundaries [15-20]. The muscular-elastic layer, adjacent to the media (also called the Jores' layer), is separated from the media by the internal elastic lamina. The innermost intimal layer, adjoining the arterial lumen, is separated from the muscular-elastic layer by the internal limiting membrane. This innermost intimal layer is also called as elastic-hyperlastic [17], connective-tissue [19, 21-24], juxtaluminal [20], or proteogly‐ can-rich layer [21]; it is located between the internal limiting membrane and the endothelial lining (Figure 1).

**Keywords:** Smooth muscle cells, Pericyte-like cells, 3G5 antigen, 2A7 antigen, Arterial wall,

The cell composition of the human arterial intima has been intensely studied but is still not well understood [1]. The majority of cell population in normal and atherosclerotic intima is represented by cells expressing α-actins, which are thought to be smooth muscle cells [2]. According to the current paradigm, smooth muscle cells show striking plasticity responding to microenvironment signals and thus can be presented by different phenotypes [3-7]. Immune-inflammatory cells also reside in the intima of healthy arterial walls [8]. Resident immune-inflammatory cells (macrophages, lymphocytes, and dendritic cells) represent only a minority of the subendothelial cell population, but their proportion increases during the development of atherosclerotic lesions, reaching up to 20% of the total cell content [9].

Some antigens, which are absent in medial smooth muscle cells, were detected in intimal smooth muscle cells [10-13]. In particular, using 3G5 antipericyte antibody, presence of stellateshaped pericyte-like resident cells in normal and atherosclerotic human aortic intima has been found [10, 11]. In all analyzed aortic tissue specimens, 3G5+cells were found to account for more than 30% of the total intimal cell population of undiseased intima. In the atherosclerotic lesions, the number of 3G5+ cells becomes notably lower than that in undiseased intima [11]. The use of 2A7 antibody that identifies "activated" pericytes revealed the presence of 2A7+ cells in atherosclerotic plaques, while no 2A7+ cells were detected in normal intima [12]. The strongest correlation was established between the number of pericyte-like cells and the content of intimal lipids [12]. The correlation coefficients between the number of pericyte-like cells and collagen content and intimal thickness were greater than the correlation coefficients for smooth muscle cells. On the basis of these findings, pericyte-like cells but not smooth muscle cells or other cell types have been declared to be the key cellular element driving the formation of

The present chapter aims to detail the abovementioned issues. The present chapter also aims to promote a view that α-smooth muscle actin+ pericyte-like cells represent the key players in

The wall of large arteries consists of three layers, namely, the tunica intima, the tunica media, and the tunica adventitia. Furthermore, the tunica intima of the adult human aorta consists itself of two layers separated by distinct boundaries [15-20]. The muscular-elastic layer, adjacent to the media (also called the Jores' layer), is separated from the media by the internal

Intima, Atherosclerosis, Atherogenesis

**1. Introduction**

204 Muscle Cell and Tissue

atherosclerotic lesions [14].

the development of atherosclerotic lesions.

**2. Structural organization of human aortic intima**

It is well known that the thickness of the intima is greater in atherosclerotic lesions than in grossly normal areas, with intimal thickness reaching the maximum in atherosclerotic plaques. In fatty streak, the thickness of the muscular-elastic layer is the same as in uninvolved intima, while in atherosclerotic plaque, it is only 11% greater than in the normal intima [25]. In contrast to the muscular-elastic layer, the thickness of the proteoglycan-rich layer increases consider‐ ably in atherosclerotic plaque, forming an intimal protrusion into the lumen, which reduces blood flow through the aorta. On average, in fatty streak, the thickness of the proteoglycanrich layer is almost two times and in the plaque almost four times as high as that in uninvolved intima [25]. Sometimes, the thickness of the proteoglycan-rich layer in the plaque can be 10 to 20-fold as high as that in a normal vessel [25].

**Figure 1.** The intima is separated from the media by the internal elastic lamina. The innermost proteoglycan-rich sub‐ layer of the human intima is separated from the muscular-elastic layer, adjacent to the media, by the internal limiting membrane. Intimal layers differ from each other in cell arrangement and by intercellular matrix organization. The muscular-elastic sublayer consists of several rows of longitudinally arranged elongated cells separated by elastic fibers, also longitudinally oriented. The connective tissue fibers of the proteoglycan-rich layer have no definite orientation to the vessel axis, and its cell population is morphologically heterogeneous, as was described as far as in the nineteenth century [24]. Histological and histochemical observations showed that in the normal intima, the muscular-elastic layer contains much more elastic fibers than the proteoglycan-rich layer, while the proteoglycan-rich layer contains more collagen and reticulin fibers [20, 23]. The layers differ from each other by the composition of glycosaminoglycans [20].
