Endothelial Cell Senescence Accelerates Atherosclerosis

Atherosclerosis, a condition in which fatty lesions form to narrow, weaken, and distort blood vessel walls, might be primarily thought of as a condition of macrophage dysfunction. The innate immune cells called macrophages are responsible for clearing out unwanted lipids from blood vessel walls. Unfortunately, the growing prevalence of oxidized lipids and an inflammatory environment arising in later life causes macrophages to falter at this task. Macrophages become inflammatory rather than helpful in the lesion environment, then are overwhelmed and die, but are still attracted in ever greater numbers to swell the size of the lesion.

Researchers have shown that some of these inflammatory and dysfunctional macrophages are senescent, and that removing them via the use of senolytic therapies helps to slow the progression of atherosclerosis in animal models. In today's open access paper, the role of senescent endothelial cells in blood vessel walls is considered. Senescent cells secrete inflammatory signals, so any population of senescent cells in the vicinity of an atherosclerotic lesion will make things worse by biasing macrophages towards adopting an inflammatory, unhelpful state, rather than working on repair of the lesion.

Given that, it is unclear as to which of the populations of senescent cell types in and around atherosclerotic lesions are most influential on the progression of the condition and growth of lesions, as present senolytic treatments will destroy all of them at the same time. It is a question that may not matter all that much at the end of the day, however. The practical road ahead is to produce senolytic therapies that can reliably and safely remove as high a proportion of senescent cells as possible from every tissue in the body.

Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis

A striking feature of cellular senescence is a stable cell cycle arrest, which prohibit the replication of damaged cells and consequently limit the tissue damage and resist tumorigenesis in the short-term. However, senescent cells become harmful in the long term, especially through secreting soluble factors including cytokines, chemokines, and matrix proteases, called senescence-associated secretory phenotype (SASP). Eliminating senescent cells prevents age-related organ dysfunction in the heart and kidney, and notably, expands the lifespan in mice. Also, senescent cell-depletion and senolytic agents that preferentially kill senescent cells improved physical function and showed beneficial effects in age-related diseases such as osteoarthritis and atherosclerosis. These findings strongly suggest the critical and causative role of cellular senescence in age-related diseases.

Senescence of vascular cells is involved in age-related vascular dysfunction including atherosclerosis. Senescent vascular cells have been detected in atherosclerotic plaque, and eliminating senescent cells prevented the progression of atherosclerosis. Also, crucial and causative roles of vascular smooth muscle cell senescence in atherosclerosis have been reported. However, a role of endothelial cell (EC) senescence in atherogenesis remains to be elusive, though potential role of senescent EC in atherosclerosis was reported. By utilizing endothelial progeroid mice, we identified EC senescence promotes atherosclerosis potentially through EC hyper-inflammability due to epigenetic alteration.

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