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 reduce lesion cellularity and promote 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 proinflammatory environment and lesion instability. Here, we 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 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. In the setting of excess cholesterol and fat, inflammatory pathways of the innate immune system are aberrantly activated. It is widely believed that oxidative modifications of the phospholipid and protein moieties of low- and very–low-density lipoproteins trigger conserved nonspecific scavenging pathways in macrophages and dendritic cells. This initiates what is at first considered a protective pathway to remove unwanted and potentially cytotoxic remnants and debris. However, during the decades of life wherein circulating low- and very–low-density lipoprotein cholesterol are in excess, this protective response turns into a chronic state of inflammation that recruits additional inflammatory cells and activates vascular cells to promote lesion expansion. During the progression of atherosclerosis, like in many other diseases, there is a constant turnover of cells within and surrounding the plaque. The identification …