Endocrine Abstracts (2004) 7 P213

Local regeneration of glucocorticoids by 11betaHSD-1 within the vessel wall modulates angiogenesis

GR Small, AR Dover, PWF Hadoke & BR Walker

Endocrine Unit, University of Edinburgh, Edinburgh, UK.

Angiogenesis, which is tightly regulated in health and disturbed in many diseases, is inhibited by glucocorticoids. Local glucocorticoid availability within the vessel wall is determined by the pair of enzymes 11beta-hydroxysteroid dehydrogenase type 1 and 2 (11HSD-1 and 2) that catalyse the interconversion of active glucocorticoid (corticosterone in mice, cortisol in humans) with inactive 11-dehydrocorticosterone or cortisone. We hypothesized that regeneration of active glucocorticoids by 11HSD-1 influences angiogenesis.

8-10 week old, male C57Bl6 wild type, and 11HSD-1 homozygous null (-/-), mice were used. Angiogenesis was examined in vitro in aortic rings cultured in Matrigel for 7 days and in vivo in polyurethane sponges implanted subcutaneously for 3 weeks. The sponges contained silicone pellets impregnated with steroids.

In wild type mice aortic rings in vitro, conversion of 11-dehydrocorticosterone to corticosterone was confirmed by HPLC; both corticosterone and 11-dehydrocortisone were angiostatic [vehicle 160 plus/minus 11 vessels; corticosterone (600 nanoMolar) 98 plus/minus 8, p<0.02; 11-dehydrocorticosterone (600 nanoMolar) 89 plus/minus 14, p<0.01], and these effects were abolished by the glucocorticoid receptor antagonist RU38486 (1microMolar). Pharmacological inhibition (carbenoxolone 1microMolar) and transgenic deletion of 11HSD-1 had no effect on the angiostatic activity of corticosterone but abolished the effect of 11-dehydrocorticosterone. In vivo, both cortisol and cortisone inhibited angiogenesis in sponges from wild type mice [vehicle 2.92 plus/minus 0.17 [Chalkley count (Cc)]; cortisol 0.56 plus/minus 0.27Cc, p<0.0001]. Cortisol but not cortisone was angiostatic in sponges in 11HSD-1 (-/-) mice [wild type plus cortisone 0.04 plus/minus 0.16Cc, 11HSD-1 (-/-) plus cortisone 2.83 plus/minus 0.23Cc, p<0.0001].

Thus, 11HSD-1 influences vascular structure by reactivating inert metabolites into angiostatic glucocorticoids. By contrast, inactivation of glucocorticoids by 11HSD-2 appears unimportant in these conditions. 11HSD-1 is induced by inflammatory cytokines, so that this mechanism may influence vascular remodelling following injury and ischaemia, and offers a potential pharmacological target to regulate angiogenesis.

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