Abstract
Endothelial cell senescence contributes to vascular inflammation and age-related pathology; however, the upstream drivers and secretory programs remain incompletely understood. This thesis investigates inflammatory signalling and secretory behaviour in human umbilical vein endothelial cells (HUVECs) rendered senescent by replicative ageing, hyperglycaemic conditions, and TNF-α stimulation. The secretory profiles under these conditions were examined; in addition, proteomic secretome analysis was conducted for the TNF-α–stimulated model to provide contextual breadth.Using in vitro models, cytokine/chemokine release, receptor involvement, and calcium dependence were assessed through complementary biochemical assays and receptor-focused perturbations. Secretome profiling was explicitly applied to TNF-α–stimulated HUVECs.
The findings are consistent with an inflammatory program in senescent endothelium. The results suggest a probable role for calcium influx in IL-8 secretion and indicate that TNFR1 may exert a more dominant influence than TNFR2 in driving this response. These inferences are confined to the experimental systems and conditions tested, and the proteomic results are presented as contextual evidence for the TNF-α model rather than as generalizable across all senescence paradigms.
Collectively, the work refines the current understanding of endothelial senescence–associated secretions and delineates specific signalling nodes, calcium influx and TNF receptor usage that merit targeted mechanistic investigation.
| Date of Award | 9 Dec 2025 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | David Stephens (Supervisor) & Harry H Mellor (Supervisor) |