Atherosclerotic and restenotic lesions develop as a result of an excess inflammatory
response to vascular injury. Glucocorticoid hormones have widely-recognised
anti-inflammatory and anti-proliferative properties which appear to make them ideal
candidates for inhibition of vascular lesion development. Indeed, administration of
glucocorticoids to experimental animals does inhibit the growth of vascular lesions in
some models. In addition, glucocorticoids are currently being trialled clinically as
anti-restenotic agents. However, glucocorticoid excess in patients, either as a result
of Cushing’s syndrome or chronic steroid therapy, is associated with enhanced CVD
risk. Therefore, the effects of glucocorticoids on vascular lesion development remain
imperfectly understood.
The overall objective of these studies was to explore the influence of endogenous and
exogenous glucocorticoids on vascular lesion development using murine models of
atherosclerosis (ApoE-/- mice fed a “western” diet) and neointimal hyperplasia (wireinduced
femoral artery injury). The work described in this thesis addresses the
hypothesis that glucocorticoids are pro-atherogenic, yet anti-restenotic.
Mice were bilaterally adrenalectomised to investigate the role of endogenous
glucocorticoids on vascular lesion development. Removal of the adrenal glands had
no influence on atherogenesis or neointima development. The influence of
exogenous glucocorticoids on lesion development was assessed by orally
administering dexamethasone (0.1 or 0.8mg/kg/day). Atherosclerotic lesion burden
was augmented by dexamethasone administration. Conversely, fibro-proliferative
neointimal proliferation was inhibited by dexamethasone. However, this effect was
obscured by thrombotic lesion development. It was proposed that this thrombotic
effect is attributable to increased plasminogen activator inhibitor-1 (PAI-1), which
was tested using PAI-1 deficient mice. Although PAI-1 was found to mediate the
systemic pro-thrombotic effect of dexamethasone, it is not required for the enhanced
development of thrombotic lesions at the site of intra-luminal injury. These results suggest that physiological levels of endogenous glucocorticoids play a
limited role in vascular lesion development. Conversely, although exogenous
glucocorticoids inhibit fibro-proliferative intimal hyperplasia, they appear to have
significant detrimental influences on lesion development, augmenting atherosclerosis
and inducing thrombotic neointimal lesion formation following vascular injury.
Further research is therefore required to improve the cardiovascular outcome of
patients requiring glucocorticoid therapy and for the use of glucocorticoids as antirestenotic
agents
