**12. Fibrosis (synthesis and accumulation of extracellular matrix)**

Accumulation of the extracellular matrix and formation of the connective tissue cap are the most clinically significant atherosclerotic manifestations. The total collagen content increases preferentially in the proteoglycan-rich layer but not in the muscular-elastic layer [25]. In uninvolved intima, cells producing collagen type I, the main interstitial collagen accumulated in atherosclerotic plaques, were not found [53]. In the proteoglycan-rich layer of atherosclerotic lesions, collagen-producing cells account from 6% (initial lesions) to 18% (fatty streaks) of total cell population [53]. These findings agree with immunohistochemical data on the localization of various collagen types in atherosclerotic lesions [25, 75, 76]. It was demonstrated that collagen is accumulated predominantly in the juxtaluminal intima.

The formation of the initial atherosclerotic lesions coincides with the emergence of cells producing type collagen I, the major interstitial collagen, which is accumulated in the cap of an atherosclerotic plaque. Formation of fatty streaks is accompanied by a considerable increase in the proportion of collagen-producing cells. Fibrollpid plaques have the maximum content of collagen-synthesizing cells, while in fibrous plaques the proportion of these cells is signifi‐ cantly lower, being comparable to that in initial lesion. Thus, in the sequence initial lesions fatty streak - fibrolipid plaque fibrous plaque, a "splash" of synthetic activity of cells with the maximum in lipid-rich lesions (fatty streaks and fibrolipid plaques) has been detected [53].

Hypersecretion of extracellular matrix may be a cause or a consequence of disintegration of the intimal cellular system in atherosclerotic lesions. In initial lesions, where the cellular network is preserved, collagen-producing cells are not numerous and are integrated into a network [53]. The network is destroyed in fatty streaks and atherosclerotic plaques. The proportion of collagen-producing cells in these lesions is higher than in initial lesions, and the cells are located at the sites of the network disintegration [53]. This suggests that synthetic activity of cells increases considerably after they have lost contact with neighboring cells.
