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Amartey, Jason (2024) Control of collateral formation as a therapeutic for cardiovascular disease. PhD thesis, University of Nottingham.

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Abstract

Peripheral arterial disease (PAD) leads to tissue ischaemia due to vascular insufficiency. In response to this ischaemia, circulating monocytes produce vascular endothelial growth factor (VEGF-A), a crucial regulator of angiogenesis. Monocytes exhibit increased overexpression of the anti-angiogenic VEGF-A isoform, termed VEGF-A165b which is generated by alternative splicing of the VEGF gene. VEGF splicing is under the control of phosphorylation of serine/arginine splicing factors (SRSFs), orchestrated by splicing factor kinases like serine-arginine protein kinase 1 (SRPK1) and CDC-like kinase (CLK). While the role of these kinases has been established in other cell types, their role in monocytes remains relatively unknown.

To address this, this thesis delves into the impact of inhibiting VEGF165b using antiVEGF165b antibodies, as well as consequences of inhibition of SRPK1 and CLK, in monocyte mediated revascularisation. These studies used a variety of in vitro and in vivo experiments such as a Transwell Endothelial Migration assays to understand the effect of monocytes on cell recruitment and migration. A hind limb ischaemia (HLI) model in obese and diabetic rodents was utilised, aiming to understand the potential roles of SRPK1 and CLK in monocytes and their influence on the process of revascularisation.

Results confirmed that VEGF165b inhibited endothelial cell migration and specific antiVEGF165b antibodies and inhibition of SRPK and CLK could reverse this inhibition. Diabetic studies using Zucker Diabetic Fatty rats and obese C57Bl6J mice that were treated with a humanised antiVEGF165b antibody had a significantly faster blood flow recovery compared to the control groups. Obese C57Bl6J mice treated with the SRPK1 inhibitor, SPHINX31 also had a significantly faster revascularisation compared with the control group.

These results indicate that targeting the antiangiogenic isoform VEGF165b or the splicing events that lead to the generation of this isoform could be potentially useful as a novel therapeutic strategy for PAD. Further research, particularly, in vivo work is required to investigate the clinical applications of the antibodies and compounds in this thesis. However, this body of work contributes to the growing body of knowledge in the field, offering a potential breakthrough in the development of targeted interventions that could significantly impact the lives of individuals grappling with the challenges of PAD.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Bates, David Benest, Andrew
Keywords:	Vascular endothelial growth factor; Vascular endothelial growth factor antibodies; SRPK1; CLK; Revascularisation inhibition
Subjects:	W Medicine and related subjects (NLM Classification) > WG Cardiocascular system
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID:	78268
Depositing User:	Amartey, Jason
Date Deposited:	17 Jul 2024 04:40
Last Modified:	17 Jul 2024 04:40
URI:	https://eprints.nottingham.ac.uk/id/eprint/78268

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