**16. Concluding remarks**

The above-presented data allows us to suggest sequence events responsible for the initiation and the progression of atherosclerotic process. Modified LDL or/and their associates enter subendothelial intima from the blood. LDL associates or LDL-containing complexes stimulate phagocytosis, which reduces intercellular communication. LDL enters the cells via a pathway other than regulated receptor lipoprotein uptake and induces intracellular lipid accumulation. This lowers cAMP and elevates cGMP, stimulating lipid accumulation, cell proliferation, as well as synthesis and secretion of the extracellular matrix. Such a situation is typical of initial atherosclerotic changes in the intima. Further accumulation of lipids internalized by phago‐ cytosis leads to isolation of cells, disruption of cell-to-cell contacts, and disintegration of the cellular network characteristic of uninvolved intima. Foam cells laden with lipids appear. Further lipid accumulation in intimal cells and destruction of cell-to-cell contacts stimulate cell proliferation and extracellular matrix production. This is typical of pronounced lipid-rich lesions (fatty streak and fibrolipid plaque). Secreted collagen and other components of the extracellular matrix surround the matrix-producing cells and isolate them from other neigh‐ boring cells; this eventually leads to disintegration of the cellular network. The intensity of the major atherosclerosis-related processes (intracellular lipid accumulation, cell proliferation, and extracellular matrix production) decreases considerably. This occurs in a fibrous plaque.

Proceeding from this concept, intracellular lipid accumulation induced by modified LDL is the crucial event of atherogenesis. Lipid accumulation stimulates the major atherosclerotic manifestations; at the same time, associates of modified LDL destroy the cellular network in the intima by stimulating phagocytosis. This leads to the formation of pronounced lipid-rich lesions, namely, fatty streaks or fibrolipid plaques, where the intensity of atherogenic mani‐ festations at the cellular level is maximal.

The intensity of cell functions activated in atherosclerosis is similar in uninvolved intima and atherosclerotic plaques. However, there is a principal difference in the state of cellular systems in these zones. Although functionally the cellular system in a fibrous plaque is similar to that of uninvolved intima, structurally it is changed to the extent indicating an irreversible transformation. Therefore, transformation of fibrous plaque to uninvolved intima is impossi‐ ble. Clinically, it is unlikely that fibrous plaque is dangerous, since it is a stable, low-activity formation.

The situation is completely different in lipid-rich lesions, specifically in a fibrolipid plaque (atheroma). This is an unstable lesion with maximally or near-maximally active cellular processes. Clinically, these lesions are most dangerous, since they rapidly develop, and their growth leads to so-called rupture of the plaque which is accompanied by critical local changes in homoeostasis resulting in thromboembolic events, which is the cause of vascular catastro‐ phes such as myocardial infarction, stroke, sudden death, etc. However, fibrolipid plaques and especially initial lesions are probably reversible, since changes in their cellular system presumably are not irreversible. Based on the suggestion that lipid accumulation is the key event in the initiation and development of atherosclerotic lesions, one may assume that prevention of lipid accumulation and removal of excessive fat from cells are most effective approaches to the prevention and reversion of atherosclerotic lesions preceding the fibrous plaque.

The above-provided data is indicative that α-smooth muscle actin+ pericyte-like cells represent the key players in the development of atherosclerotic lesions. Obviously, further studies are needed to understand the mechanisms of interaction between α-smooth muscle actin+ pericyte-like cells with other cell types during atherogenesis and evaluate how functioning of α-smooth muscle actin+ pericyte-like cells affects immune-inflammatory processes in athero‐ genesis. The involvement of pericyte-like cells in the regulation of immune-inflammatory processes in atherosclerosis is supported by a finding of widespread expression of HLA-DR antigen by the vast majority of cells residing in the arterial subendothelial space [98].
