Premature Vascular Senescence during Diabetic Retinopathy

Abstract

Cellular senescence is the permanent state of growth arrest with significant phenotypic changes including the senescence-associated secretory phenotype (SASP) and triggered by mechanisms such as telomere shortening and DNA damage. Diabetes is associated with endothelial dysfunction, which is characterised by increased vascular permeability, deficit in blood perfusion, vessel loss and increased inflammation. Cellular senescence has been implicated in the pathogenesis of diabetes; however, a role for cellular senescence in diabetic retinopathy is unclear. Therefore, the aim of this study is to investigate the senescence profile of human retinal microvascular endothelial cells (HRMECs), to elucidate how this is affected by the diabetic milieu.

HRMECs undergo replicative senescence in vitro and they acquire gene and protein expression profiles that are characteristic of a senescent phenotype. Senescent HRMECs show a SASP signature, changes in organelle profiles, loss of endothelial function and metabolic impairment.

Chronic exposure to high glucose (25mM D-glucose) induces premature senescence in HRMECs. The accelerated senescence programme was characterised by enlarged cellular and nuclear size, upregulation of p53 and CCL2 (MCP1), increased mitochondrial mass but, with alterations in mitochondrial cristae ultrastructure and decreased cellular bioenergetics both glycolysis and oxidative respiration.

The aged mouse retina shows cellular senescence, accompanied by visual dysfunction and structural changes. The diabetic milieu, both hyperglycaemia and ischaemia, lead to accumulation of senescent cells in the retina, including the retinal vasculature.

Senolytic drugs are investigated as a therapeutic approach for elimination of senescent HRMECs. Navitoclax was found to be an effective senolytic for HRMECs in vitro.

Date of Award	Dec 2020
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	National Eye Research Centre
Supervisor	Reinhold Medina (Supervisor) & Alan Stitt (Supervisor)