Abstract
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 ofSENEX (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.
Highlights
Endothelial cell senescence is linked to both aging and vascular pathologies
The DNA damage response (DDR) response, as identified by the marker γH2A.X, was upregulated within 30mins of H2O2 treatment (Figure 1E) and remained elevated for approximately the 2 hours, returning to baseline thereafter. Consistent with this we found an upregulation of p53 and p21 protein levels, 48 and 96 hrs following H2O2 treatment, at a time when the senescent phenotype is detected (Figure 1F)
By day 8 (Figure 6C) the ratio of anti-inflammatory to pro-inflammatory senescent cells, as assessed by adhesion molecule expression, was approximately 1:1 and this was similar on day 16 (Figure 6D). These results suggest that oxidative stress induces a stable mosaic inflammatory phenotype of senescent endothelial cells (ECs), judged either by neutrophil adhesion or adhesion molecule expression, where the anti-inflammatory phenotype and the pro-inflammatory phenotype exist in concert
Summary
Endothelial cell senescence is linked to both aging and vascular pathologies. Oxidative stress results from the generation of ROS and vascular aging is associated with an increase in ROS [8] and these species, which include superoxide anion radicals and hydrogen peroxide (H2O2) are found in all layers of the diseased arterial wall. EC at the sites of bifurcations and branching are subjected to increased and chronic changes in shear forces [9]. At these points there is increased EC turnover likely as a consequence of the www.impactaging.com
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