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Hashmat, Arshad (2024) Elucidating the role of hyperglycaemia in endothelial cell and pericyte morphology, function and crosstalk, and blood-brain barrier integrity. MRes thesis, University of Nottingham.

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Abstract

Diabetes is a complex metabolic disorder associated with a myriad of neurovascular complications, including disruption of the blood-brain barrier (BBB) and endothelial dysfunction. The intricate relationship between hyperglycaemia and cells of the neurovascular unit is of significant importance and yet remains inadequately understood. This study aims to delve into the impact of elevated glucose levels on three key areas: endothelial cell function, pericyte-endothelial interaction, and the integrity of the BBB in vitro.

Our study employed human brain microvascular endothelial cells and pericytes, cultured under normal glucose conditions (5mM) and high glucose conditions (25mM). A comprehensive evaluation of endothelial cell morphology, stress fibre formation, DNA damage responses, tube formation, and the secretome profile was performed. Furthermore, pericytes were exposed to endothelial cell-conditioned media, and the consequent cytokine production was measured. An in vitro BBB model was harnessed to assess the localization of tight junction proteins and paracellular/transcellular permeability.

Exposure to high glucose levels led to cytoskeletal remodelling in endothelial cells, although it did not noticeably modify cell morphology or directly cause DNA damage. The endothelial secretome exhibited an increase in angiogenic factors under high glucose conditions. Interestingly, pericytes exposed to high glucose-conditioned endothelial secretome displayed reduced expression of inflammatory cytokines. High glucose conditions also resulted in increased localization of tight junction proteins and augmented transcellular permeability across the BBB model.

Our findings stress that acute hyperglycaemia, while capable of initiating internal cellular changes, does not drastically alter the apparent phenotype of endothelial cells. Nevertheless, it significantly influences their secretome profiles, leading to the disruption of pericyte-endothelial crosstalk and compromising the integrity of the BBB. This research sheds light on the neurovascular dysfunction associated with diabetes and proposes multiple potential targets for the development of therapeutic interventions aimed at mitigating these complications.

Item Type:	Thesis (University of Nottingham only) (MRes)
Supervisors:	Bayraktutan, Ulvi Sprigg, Nikola
Keywords:	Hyperglycaemia, Neurovascular Unit (NVU), Human Brain Microvascular Endothelial Cells (HBMECs), Pericytes (PCs), Blood-brain barrier (BBB), Tubulogenesis, Secretome, Angiogenic and Cytokine expression
Subjects:	W Medicine and related subjects (NLM Classification) > WK Endocrine system
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Clinical Sciences UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID:	77557
Depositing User:	Hashmat, Arshad
Date Deposited:	19 Jul 2024 13:10
Last Modified:	19 Jul 2024 13:10
URI:	https://eprints.nottingham.ac.uk/id/eprint/77557

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