Mechanisms and consequences of endothelial cell senescence

Abstract

Endothelial cells are located at the crucial interface between circulating blood and semi-solid tissues and have many important roles in maintaining systemic physiological function. The vascular endothelium is particularly susceptible to pathogenic stimuli that activate tumour suppressor pathways leading to cellular senescence. We now understand that senescent endothelial cells are highly active, secretory and pro-inflammatory, and have an aberrant morphological phenotype. Moreover, endothelial senescence has been identified as an important contributor to various cardiovascular and metabolic diseases. In this Review, we discuss the consequences of endothelial cell exposure to damaging stimuli (haemodynamic forces and circulating and endothelial-derived factors) and the cellular and molecular mechanisms that induce endothelial cell senescence. We also discuss how endothelial cell senescence causes arterial dysfunction and contributes to clinical cardiovascular diseases and metabolic disorders. Finally, we summarize the latest evidence on the effect of eliminating senescent endothelial cells (senolysis) and identify important remaining questions to be addressed in future studies.

Fig. 1 |. Morphological changes in senescent endothelial cells.

Senescent cells (shown in blue) become enlarged and adhesion to basement membranes is increased, thereby hindering their alignment to laminar shear stress.

Fig. 2 |. Exposure of endothelial cells to circulating and endogenous stimuli.

Owing to their anatomical position, endothelial cells are continually exposed to circulating biochemical factors and haemodynamic forces. These factors include oxygen, nutrients (e.g. amino acids, glucose, hormones (e.g. insulin, angiotensin II, endothelin 1 and lipids) and cytotoxic drugs (e.g. chemotherapeutics). Haemodynamic forces include low and oscillatory shear stress at bifurcations and curvature points, as well as high and pulsatile pressure in other regions. Endothelial cells are also exposed to inflammatory cytokines and reactive oxygen species (ROS) derived from circulating immune cells and directly from every organ and tissue. This combination of unique damaging stimuli renders endothelial cells particularly susceptible to cellular senescence. Moreover, these interactions are prolonged due to the long-lived nature of endothelial cells, particularly in large arteries where they are rarely replaced by progenitors.

Fig. 3 |. Mechanisms of endothelial cell senescence induced by damaging stimuli.

Circulating and endogenous stimuli result in telomeric and non-telomeric DNA damage and alter energy sensor pathways, such as those involving the sirtuins (SIRT1, SIRT3 and SIRT6). Consequently, endothelial cells activate tumour suppressor pathways (tumour antigen p53–cyclin-dependent kinase inhibitor 1A (also known as p21) and retinoblastoma protein (pRb)–cyclin-dependent kinase inhibitor 2A (also known as p16), which reprogrammes endothelial gene expression resulting in a host of cellular and molecular changes. For example, endothelial cells lose their proliferative potential and become senescent (blue cells); activate the senescence-associated secretory phenotype (SASP), which includes inflammatory pathways such as nuclear factor NF-kappa B (NF-κB) and secretion of inflammatory cytokines and reactive oxygen species (ROS); and attenuate the production of critical vasoactive molecules (e.g. nitric oxide (NO)). Collectively, the cellular and molecular changes promote arterial dysfunction resulting in cardiometabolic diseases. CXCL11, C-X-C motif chemokine 11; DDR, DNA damage response; MMPs, matrix metalloproteinases; PAI-1, plasminogen activator inhibitor 1; TGF-β, transforming growth factor-β.