Inflammation, local vascular glucocorticoid regulation and endothelial function

• Main Author: Dover, Anna Rachel
• Published: University of Edinburgh 2006
• Subjects: 615.1
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.649687

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 <i>in vitro</i>, and in the perfused mouse hindquarter <i>in vivo</i>. 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 <i>in vitro</i> but was shown to be a predominant reductase <i>in vivo</i>. 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 <i>in vitro</i>. Systemic <i>in vivo</i> LPS administration resulted in a modest increase in 11β-reductase activity in aortic rings <i>ex vivo</i>, but did not alter 11β-reductase activity in the perfused hindquarter <i>in situ</i>. These data suggest that up-regulation of 11βHSD1 reductase is unlikely to be a significant accompaniment of vascular inflammation in healthy arteries <i>in vivo</i>. 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 <i>in vivo.</i>