Research Article: Age-associated stresses induce an anti-inflammatory senescent phenotype in endothelial cells

Date Published: December 12, 2013

Publisher: Impact Journals LLC

Author(s): Paul R. Coleman, Garry Chang, Gabor Hutas, Matthew Grimshaw, Mathew A. Vadas, Jennifer R. Gamble.



Age is the greatest risk factor for cardiovascular disease. In addition, inflammation and age (senescence) have been linked at both the clinical and molecular levels. In general, senescent cells have been described as pro-inflammatory based on their senescence associated secretory phenotype (SASP). However, we have previously shown that senescence induced by overexpression of SENEX (or ARHGAP18), in endothelial cells results in an anti-inflammatory phenotype. We have investigated, at the individual cellular level, the senescent phenotype of endothelial cells following three of the chief signals associated with ageing; oxidative stress, disturbed flow and hypoxia. All three stimuli induce senescence and, based on neutrophil adhesion and expression of the adhesion molecules E-selectin and VCAM-1, a population of senescent cells is seen that is resistant to inflammatory stimuli and thus we define as anti-inflammatory. The proportion of anti-inflammatory cells increases with time but remains stable at approximately 50% by eight days after induction of senescence, suggesting that these are stable phenotypes of endothelial cell senescence. Similar to other senescent cell types, p38MAPK blockade inhibits the development of the pro-inflammatory phenotype but unique to EC, there is a corresponding increase in the number of anti-inflammatory senescent cells. Thus stress-induced senescent endothelial cells display a mosaic of inflammatory phenotypes. The anti-inflammatory population suggests that senescent endothelial cells may have an unique protective role, to inhibit uncontrolled proliferation and to limit the local inflammatory response.

Partial Text

Endothelial cell senescence is linked to both aging and vascular pathologies. With age there is an increase in the markers of senescence in the vasculature, including senescence associated β-galactosidase (SA β-gal) and p16. Increased numbers of senescent endothelial cells (ECs) are found in atherosclerotic plaques of human aorta and coronary arteries [1], in coronary vessels of patients with ischaemic heart disease [2], in vessels from diabetic rats [3] and EPC from diabetics undergo heightened senescence postulated to be one of the causes of the impaired neovascularisation seen in diabetes [4]. Furthermore, many stimuli linked to cardiovascular disease (CVD) induce senescence, for example, asymmetrical dimethylarginine, and homocysteine [5], and reactive oxygen species (ROS) [6]. Senescent ECs have also been identified in the tumor vasculature in glioma [7].

One of the critical hallmarks of the endothelium is the ability to support and resolve inflammatory responses. Given the prominent role of the endothelium in both inflammation and in the ageing process it is important to understand how the endothelium responds to this situation. Endothelial senescence has been connected from in vitro, in vivo, and most recently by ex vivo genomic analysis to ageing, but the functional properties of senescent EC have not been widely studied. We now show clear evidence for dynamic changes in the inflammatory phenotype of EC undergoing senescence, and importantly define an anti-inflammatory senescent phenotype, induced with a variety of stimuli that are associated with ageing.





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