[Molecular medicine and gene therapy as exemplified with arteriosclerosis and restenosis]

Atherosclerosis and its consequences account for most morbidity and mortality in Western countries. Atherosclerosis develops over a period of decades and has a complex pathogenesis. It is a disease of the intima and primarily involves four cell types, i.e. endothelial and vascular smooth muscle cells, monocytes and platelets. In recent years, elucidation of the cellular and molecular mechanisms of these cells, and their alterations by cardiovascular risk factors and in atherosclerosis, has markedly expanded knowledge of this disease. In particular, it became clear that endothelial cells play a crucial role in the regulation of platelet function and coagulation, as well as vascular tone and structure. Interestingly, endothelial dysfunction occurs early on in the presence of cardiovascular risk factors such as hyperlipidemia, hypertension and diabetes. This could lead to adhesion of circulating platelets and monocytes, increased accumulation of lipids in the subintima, increased contraction, migration and proliferation of vascular smooth muscle cells. The fact that atherosclerosis develops only in some but not in other parts of the circulation, however, has rarely been considered. With the development of molecular biology it has now become possible to clone differentially expressed genes in vessels with or without atherosclerosis; this in turn makes it possible to characterize better the molecular and cellular mechanisms of the disease. The search for such candidate genes could form the basis for future genetic interventions. This therapeutic approach is likely to assume clinical importance, particularly in monogenetic diseases (i.e. familial hypercholesteremia), while its use in complex polygenetic diseases such as atherosclerosis is more difficult. Restenosis, however, may be accessible to gene therapy earlier on as it is accessible to local gene transfection.