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.
