Apoptosis in the vasculature: mechanisms and functional importance

Abstract

Apoptotic death has now been recognized in a number of common and threatening vascular diseases, including atherosclerosis. Interest in apoptosis research relates to the fact that apoptosis, in contrast to oncosis, is a highly regulated process of cell death which raises the hope for the development of specific therapeutic strategies to alter disease progression. This review summarizes the mechanisms involved in vascular endothelial and smooth muscle cell survival/apoptosis, and the potential roles of apoptotic death in atherosclerosis and restenosis. The potential effects of modulation of apoptosis in these diseases are also discussed.

Figure 1

Schematic representation of main apoptotic pathways. Activation of caspase-8 (and subsequent activation of the caspase cascade) occurs following ligation of death-signal-transmitting receptors. Caspase-9 activates cell disassembly in response to agents or insults that trigger release of cytochrome c from the mitochondria, and is activated when complexed with dATP, Apaf-1, and extramitochondrial cytochrome c to form the multi-protein “apoptosome” ensemble. Caspase-8 and caspase-9 can activate caspase-3 by proteolytic cleavage, and caspase-3 amplifies caspase-8 and caspase-9 signals into fully-fledged commitment to disassembly, therefore propagating the caspase cascade. Ligation of the death-signal-transmitting receptor TNFR may also generate signal transduction pathways leading to activation of the nuclear transcription factor NF-κB and to the induction of cytoprotective genes.

Figure 2

Schematic representation of the structural alterations and DNA fragmentation phase. DFF is composed of two subunits, DFF45 (ICAD) and DFF40 (CAD). Cleavage of DFF45 by caspase-3 activates the nuclease activity of DFF40. Other substrates for caspases include PARP and lamin.

Figure 3

Schematic drawing that shows the importance of cell-to-cell and cell-to-matrix-interactions in endothelial cell survival. The survival effect of growth factors like VEGF is dependent on cell-to-cell contact (involving VE-cadherin pathway). VE-cadherins can be upregulated by shear stress. Akt phosphorylation is central to many anti-apoptotic signalling pathways and modulates the balance between anti-apoptotic and pro-apoptotic bcl-2 family members. Pro-inflammatory stimuli, including TNF-α and IFN-γ, may interfere with matrix-dependent cell survival pathways.