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Title: Investigating the effect of Wnt proteins on VSMC behaviour and vessel remodelling during ageing
Author: Monk, Bethan Alice
ISNI:       0000 0004 6057 7709
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2016
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Cardiovascular diseases, including coronary artery disease and stroke, are the most prevalent cause of global mortality. The underlying cause of both diseases is atherosclerosis, a chronic vascular disease characterised by the formation of lipid-filled inflammatory plaques covered with a protective fibrous cap. In advanced atherosclerosis, apoptosis of vascular smooth muscle cells (VSMCs) within the fibrous cap predisposes the plaque to rupture causing thrombosis and ischemia. Therefore, therapies capable of reducing VSMC apoptosis have potential to decrease cardiovascular disease mortality. Previous work by our laboratory demonstrated that Wnt5a protein was able to rescue primary mouse VSMCs from hydrogen peroxide (H₂O₂)-induced apoptosis. Additional analyses identified that rescue was mediated via activation of β-catenin and cyclic AMP response element-binding protein (CREB) and upregulation of the pro-survival factor Wnt-1 induced secreted protein-1 (WISP-1). Work in this thesis showed that, in addition to WntSa, Wnt3a and Wnt4 proteins were expressed in atherosclerosis near VSMCs. Wnt3a, but not Wnt4, protein rescued H202-induced VSMC apoptosis, however, in contrast to WntSa, Wnt3a-mediated rescue involved β-catenin and T-cell factor (TCF) activation and WISP-2 upregulation. Interestingly, WntSa, but not Wnt3a, mediated survival was impaired in VSMCs from old mice due to loss of CREB activation. Wnt4- induced VSMC proliferation in vitro was also diminished with age, however, no difference in carotid artery ligation induced neointimal proliferation was observed in arteries from old mice. Intriguingly, flow-induced outward remodelling in the contralateral carotid artery was exaggerated with ageing and was associated with blunted upregulation of the β-cateninITCF-responsive gene AXIN-2 in aged arteries. Together these data suggest that Wnt3a, Wnt4 and Wnt5a mediate divergent effects on VSMC behaviour and are differentially affected by ageing. Furthermore, this work implies a broader role for Wnt signalling in remodelling and ageing, strengthening the need for further investigation into this pathway as a putative therapy for cardiovascular disease
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available