Control of the collateral formation of cardiovascular disease by SRPK1

Bhalla, Sohni Ria (2021) Control of the collateral formation of cardiovascular disease by SRPK1. PhD thesis, University of Nottingham.

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Abstract

Vascular insufficiency in peripheral arterial disease (PAD) results in tissue ischemia. In response, circulating monocytes produce vascular endothelial growth factor (VEGF-A), a key regulator of angiogenesis. Patients with PAD and mouse models of ischemic disease have reduced soluble frizzled related protein (Sfrp5) resulting in increased wingless-type MMTV integration site family 5a (Wnt5a) activity. Monocytes from both humans and mice overexpress the anti-angiogenic VEGF-A isoform, VEGF-A165b. VEGF splicing is regulated by the phosphorylation of serine/arginine splicing factors (SRSFs) by splicing factor kinases such as serine-arginine protein kinase 1 (SRPK1). The role of SRPK1 has been shown in multiple cell types, but the role in monocytes is unknown. Therefore, this thesis investigated the effect of SRPK1 on revascularisation using experimental hind limb ischemia (HLI) in a transgenic mouse model with monocyte specific Wnt5a overexpression (LysM-Wnt5aGain of Function) administered with an SRPK1 inhibitor. To determine the role of SRPK1 specifically in the monocytes, a novel double transgenic mouse model was generated with Wnt5a hyperactivity and SRPK1 knockout.

Monocyte specific Wnt5aGOF mice had a significantly slower blood flow recovery compared to wild type (WT) mice. This was associated with a reduced capillary and arteriolar density after ischemia in the gastrocnemius muscle. This impaired revascularisation was rescued with an SRPK1 inhibitor, SPHINX31 (post-surgery) and resulted in an increase in the capillary and arteriolar density. The impairment was due to monocyte derived SRPK1 as the revascularisation in LysM-Wnt5aGOF mice was rescued in a monocyte specific SRPK1 knockout mice (SRPK1MoKO), which matched WT mice. This was also true in a model of obesity, when mice fed on a high fat/ high sucrose (HF/HS) also showed improved blood flow recovery in monocyte specific SRPK1 knockout compared with WT mice.

These results indicate that revascularisation in ischemic mouse models are dependent on monocytic SRPK1 through an unknown mechanism. Thus, SRPK1 inhibition could be used as a potential novel therapeutic strategy for PAD.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Bates, David
McIntyre, Alan
Keywords: Peripheral arterial disease; Vascular insufficiency; Revascularisation; Tissue ischemia
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: 67072
Depositing User: Bhalla, Sohni
Date Deposited: 04 Apr 2022 10:38
Last Modified: 04 Apr 2022 10:38
URI: http://eprints.nottingham.ac.uk/id/eprint/67072

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