Background: In contrast to the well-known morphologic lesions of arteriosclerosis, the initial changes of the disease are less obvious. Commonly, functional disturbances of the endothelium, endothelial dysfunction, are suggested. On the other hand the significance of age-dependent changes in the extracellular matrix with their important role in vessel wall permeability and other features associated with arteriosclerosis should not be overlooked. New topics deal with possible infectious factors, the genetic basis of the disease and the particularities of the unstable atheroma. Objective: Alterations in nitric monoxide and endothelin-1 balance of the endothelium are the key events in the initiation of arteriosclerosis induced by oxidized lipoproteins, cigarette smoking and endotoxin. This frequently supposed mechanism contrasts with earlier opinions on the primary alterations in glycosaminoglycan metabolism and other components of the extracellular matrix against atherogenic factors like hypertension, stress and physical inactivity. Based on a survey of the literature and our own experimental experiences, these changes in connection with the morphometrically determined age-conditioned increase in vascular wall thickness and the above-mentioned new topics on arteriosclerosis were analyzed. Conclusion: The initial lesions of arteriosclerosis starting in youth seem to be fundamentally different from those beginning in old age. The first step in the development of fatty streaks in the arteries of young people is endothelial dysfunction with a decreased formation of nitric monoxide and an increased expression of adhesion molecules. In comparison the genesis of arteriosclerosis in advanced age is characterized by metabolic changes in the endothelium combined with age-conditioned alterations in the extracellular matrix resulting in faster progression of the disease in old age. The multicausal genesis of arteriosclerosis cannot be doubted even if cooperation with infectious factors cannot be excluded. The histopathologic peculiarities of unstable atheroma are described.

Background: Changes in the proteoglycan metabolism of the intima of arteries belong to the initial lesions of atherosclerosis (AS). The accumulation of proteoglycans, alterations of pericellular glycoproteins and modulations of collagen turnover also play a fundamental role in the progression of AS. They influence lipid retention, cell behavior and calcinosis. The decisive role played by the matrix metalloproteinases (MMPs) and their inhibiting factors (tissue inhibitors of metalloproteinases [TIMPs]) in these processes is not yet fully understood and therefore the subject of this overview. The causes of the abrupt change of a long-term existing stabile AS to a vulnerable plaque as well as the participation of age-related vascular wall remodeling in the progression of AS also remain open questions. Discussion: Apart from the well-known risk factors for AS, less well-known influences like the disturbances of gene expression in vascular smooth muscle cells affect an MMP/TIMP imbalance. The various consequences of this imbalance range from intima cell proliferation as an early change in AS as well as accelerated progression to the destabilization of fibrous plaques by increased collagenolysis as well as the formation of aneurysms. Infectious or toxic influences may trigger these mechanisms; an involvement of age-related vessel wall changes should also be considered. The prognostic significance of circulating MMP concentrations for the existence of instabile plaques are of great interest, as is the plaque stabilizing effect of statins by suppression of MMPs. Conclusions: MMPs navigate the behavior of vascular wall cells in different AS stages, in adaptive remodeling, in normal aging and in non-atherosclerotic vessel disease. The clinical relevance of a disturbance in the MMP/TIMP balance is demonstrated firstly by the initiation of AS due to migration and proliferation of intima cells and secondly in the collagenolysis, necrotic transformation and apoptosis of existing fibrous lesions resulting in instabile rupture proned plaques. Investigations into the genetic typing of MMPs and the results of experimental gene deficiency models have significantly contributed to the clarification of these facts.

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