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.
22 - 24 Mar 2004
British Endocrine Societies