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Title: Inflammation, local vascular glucocorticoid regulation and endothelial function
Author: Dover, Anna Rachel
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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It was hypothesised that inflammatory mediators enhance local glucocorticoid generation by 11β-hydroxysteroid dehydrogenases in intact vascular tissue with resultant impairment of endothelial cell function. 11β-Reductase and dehydrogenase activities were detected in intact mouse aorta and iliofemoral arteries in vitro, and in the perfused mouse hindquarter in vivo. 11β-reproduction was the predominant reaction direction. Use of mice with genetic inactivation of either 11βHSD1 or 11βHSD2 demonstrated that 11βHSD2 acts as an exclusive dehydrogenase. 11βHSD1 exhibited bidirectional activity in intact arteries in vitro but was shown to be a predominant reductase in vivo. These studies confirm the predominant regeneration of glucocorticoids by the 11β-hydroxysteroid dehydrogenases within the vessel wall and suggest that these isozymes play an important role in modulating intra-vascular glucocorticoid signalling. 11βHSD1 activity in cultured murine aortic smooth muscle cells was up-regulated following incubation with the pro-inflammatory cytokine IL-1β. By contrast, there was no such effect of inflammatory mediators on 11βHSD activity in intact aortic rings in vitro. Systemic in vivo LPS administration resulted in a modest increase in 11β-reductase activity in aortic rings ex vivo, but did not alter 11β-reductase activity in the perfused hindquarter in situ. These data suggest that up-regulation of 11βHSD1 reductase is unlikely to be a significant accompaniment of vascular inflammation in healthy arteries in vivo. However, the possibility remains that 11βHSD1 is up-regulated in pathological conditions associated with intense cell proliferation, such as vessel injury or atheroma. The studies presented in this thesis demonstrate that the isozymes of 11βHSD modulate local glucocorticoid concentrations with intact murine vasculature. However, glucocorticoid metabolism by the 11βHSDs in healthy murine arteries is not altered by inflammatory mediators. Finally, acute systemic variations in glucocorticoid availability do not impair endothelial cell vasomotor or fibrinolytic function in humans in vivo.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available