Intravascular glucocorticoid metabolism during inflammation and injury in mice

11 beta-Hydroxysteroid dehydrogenases ( 11 beta HSDs) catalyze interconversion of 11-hydroxy-glucocorticoids with inactive 11-keto metabolites. In blood vessel walls, loss of 11 beta HSD1 is thought to reduce local glucocorticoid concentrations, reducing the progression of atheroma and enhancing angiogenesis. Conversely, on the basis that 11 beta HSD1 is up-regulated approximately 5-fold by inflammatory cytokines in cultured human vascular smooth muscle cells, it has been proposed that increased 11 beta HSD1 during vascular inflammation provides negative feedback suppression of inflammation. We aimed to determine whether inflammation and injury selectively upregulate 11 beta HSD1 reductase activity in vitro and in vivo in intact vascular tissue in mice. In isolated mouse aortae and femoral arteries, reductase activity ( converting 11-dehydrocorticosterone to corticosterone) was approximately 10-fold higher than dehydrogenase activity and was entirely accounted for by 11 beta HSD1 because it was abolished in vessels from 11 beta HSD1(-/-) mice. Although 11 beta HSD1 activity was upregulated by proinflammatory cytokines in cultured murine aortic smooth muscle cells, no such effect was evident in intact aortic rings in vitro. Moreover, after systemic inflammation induced by ip lipopolysaccharide injection, there was only a modest ( 18%) increase in 11 beta-reductase activity in the aorta and no increase in the perfused hindlimb. Furthermore, in femoral arteries in which neointimal proliferation was induced by intraluminal injury, there was no change in basal 11 beta HSD1 activity or the sensitivity of 11 beta HSD1 to cytokine up- regulation. We conclude that increased generation of glucocorticoids by 11 beta HSD1 in the murine vessel wall is unlikely to contribute to feedback regulation of inflammation.