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Title: Does altered insulin signalling modulate vascular regeneration?
Author: Mercer, Ben N.
ISNI:       0000 0004 5356 0546
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2014
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The prevalence of insulin resistant syndromes is rising worldwide. Affected individuals are at increased risk of morbidity and premature mortality, much of which is driven by cardiovascular disease (CVD). Enhancement of vascular regeneration, using pharmacological or cell-based therapies, has been suggested as a strategy to help address these issues. Although many pathophysiological processes associated with insulin resistant syndromes are likely to impair vascular regeneration, the effect of insulin resistance per se is not established. South Asian (SA) ethnicity is associated with increased risk of CVD, and insulin resistance is thought to be a major contributor to this. We compared the angiogenic capacity of late outgrowth endothelial progenitor cells (LEPCs) from young SA men, with those from a matched group white European (WE) men. LEPC have previously been shown to offer potential as an autologous cell therapy in preclinical models of ischaemic CVD. Both groups were well matched, and free of classical cardiovascular risk factors, but the SA group were relatively insulin resistant. SA LEPCs did not augment vascular regeneration in a murine model of limb ischaemia, in contrast with WE LEPC. Akt activity, a critical modulator of angiogenesis, was reduced in SA LEPC, and we were able to rescue SA LEPC dysfunction by enhancing Akt activity. We then established the impact of insulin resistance per se on vascular regeneration, using insulin receptor haploinsufficient mice (IRKO). Indices of angiogenesis were reduced in isolated endothelial cells, aortic ring 5 segments, and ischaemic hind limb muscle. Moreover, this was associated with functional resistance to vascular endothelial growth factor (VEGF), which may have mechanistically contributed to our observations. Together, these data provide insight into how insulin resistance may promote the development of premature CVD, and show that by manipulating key growth factor signalling nodes, we can rescue impaired vascular regeneration. Furthermore, we have established that insulin resistance negatively impacts on the functional response to VEGF, and it will be important to explore the mechanisms underlying this phenomenon in future studies. It is hoped that these findings will help lead to the development of strategies to mitigate the effects of CVD in individuals with insulin resistance.
Supervisor: Cubbon, Richard M. Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available