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Title: Glucocorticoid metabolism and the vascular response to injury
Author: Macdonald, Linsay Joanne
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2008
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In order to study the influence of glucocorticoids on vascular lesion formation, a model of intra-luminal, wire-induced vascular injury in the mouse femoral artery was developed. This model caused extensive stretching of the arterial wall and denudation of the endothelium, followed by the time-dependent formation of smooth muscle-rich neointimal lesions. Systemic administration of dexamethasone by sub-cutaneous injection (1 mg/kg/day, 21 days) reduced the size of smooth muscle-rich lesions after injury, but also promoted the formation of large thrombotic lesions. These occluded the lumen, leading to a similar reduction in luminal diameter to that seen in vehicle-treated controls. In contrast, local application of cortisol at the vessel wall via sustained release from an implanted pellet (21 days), significantly reduced neointimal lesion growth when compared to contra-lateral vehicle controls, without the development of thrombotic lesions. The influence of endogenous glucocorticoid activity on neointimal proliferation in the femoral artery was assessed using administration of a glucocorticoid receptor antagonist (RU38486, via implanted pellet for 21 days) or via selective pharmacological inhibition of 11βHSD1 (60mg/kg/day via oral gavage, 14 days) and the use of mice with transgenic disruption of 11βHSD1. Neither glucocorticoid receptor antagonism nor 11βHSD1 inhibition or deletion altered neointimal lesion development after injury. These results indicate that exogenous glucocorticoids do inhibit proliferation in this model but their effectiveness depends upon whether they are administered systemically or locally at the vessel wall. Whereas the manipulation of endogenous glucocorticoid generation in the vessel wall may not represent a novel therapeutic target, the application of glucocorticoids locally at this site may be beneficial in the treatment of arterial remodelling.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available