Cell Death in the Vessel Wall: The Good, the Bad, the Ugly

Abstract

Atherosclerotic vascular disease results from an imbalance of inflammatory and vascular cell accumulation and removal in the neointimal space. When pathways that promote cell recruitment, survival and proliferation are favored over to those that activate cell death, egress and clearance, the plaque expands. In contrast, programmed cell death and the efficient clearance of apoptotic bodies by efferocytosis reduces lesion cellularity and promotes a reparative environment and lesion stability. However, should these carefully balanced pathways become disturbed, lesions can accumulate cell debris, damaged-associated molecular patterns and arrested macrophages, all contributing to the pro-inflammatory environment and lesion instability. Here, we will review the latest understanding of how cell death in the vessel wall directly coordinates the development of atherosclerosis, and what molecular signals are orchestrating these pathways. We will discuss the necessity of cell death, and the ways in which the execution of different forms of cell death can direct different outcomes in the plaque, and how promoting the effective clearance of dead cells from the lesion is looking like a promising therapeutic path forward.

Keywords: apoptosis; atherosclerosis; cell death; macrophage; necrosis.

Figure 1. Cell death during early and advanced atherosclerosis

In early atherosclerosis (top), lesion cellularity is limited via apoptosis through activation of ER stress and/or pro-apoptotic factors (i.e. Jnk1, Bax-1) or through downregulation of anti-apoptotic factors (Bcl-2, AIM, IKKα). Efficient efferocytosis via MerTK and adequate Resolvin synthesis clears apoptotic body accumulation. Other anti-inflammatory and anti-apoptotic factors (i.e. ADAM17 and TNFR2) also reduce lesion expansion. In advanced lesions (bottom), excessive apoptosis and activation of necroptosis (i.e. RIP3, MLKL) can cause release of necrotic material that may be recognized by receptors like Cecl4e and activate further apoptosis and/or inflammation. “Don’t eat me” signals presented on dying atherosclerotic cells prevent efferocytosis clearance. Defective efferocytosis via cleavage of MerTK, reduced Resolvin synthesis and/or miR-155-dependent inhibition of Bcl6 also prevent clearance of apoptotic and necrotic cells. Cell debris accumulates and necrotic core expands in advanced atherosclerosis.