The role of apoptosis in vascular disease.

Normal arteries are characterized by a low turnover of endothelial (EC) and smooth muscle cells (SMC). Different mechanisms protect the EC and SMC against apoptosis in the normal artery. In hypertension, SMC replication is increased but this is not counterbalanced by increased apoptosis, resulting in thickening of the media of arteries and arterioles. The significance of apoptosis in atherosclerosis depends on the stage of the plaque, localization and the cell types involved. Both macrophages and SMC undergo apoptosis in atherosclerotic plaques. Apoptosis of macrophages is mainly present in regions showing signs of DNA synthesis/repair. SMC apoptosis is mainly present in less cellular regions and is not associated with DNA synthesis/repair. Even in the early stages of atherosclerosis SMC become susceptible to apoptosis since they increase different pro-apoptotic factors. Moreover, recent data indicate that SMC may be killed by activated macrophages. The loss of the SMC can be detrimental for plaque stability since most of the interstitial collagen fibres, which are important for the tensile strength of the fibrous cap, are produced by SMC. Apoptosis of macrophages could be beneficial for plaque stability if apoptotic bodies were removed. Apoptotic cells that are not scavenged in the plaque activate thrombin, which could further induce intraplaque thrombosis. It can be concluded that apoptosis in primary atherosclerosis is detrimental since it could lead to plaque rupture and thrombosis. Recent data of our group indicate that apoptosis decreased after lipid lowering which could be important in the understanding of the cell biology of plaque stabilization. Copyright 2000 John Wiley & Sons, Ltd.