Endothelial cell dysfunction in mice after transgenic knockout of type 2, but not type 1, 11 beta-hydromysteroid dehydrogenase

P W F Hadoke, C Christy, Y V Kotelevtsev, B C Williams, C J Kenyon, J R Seckl, J J Mullins, B R Walker

Research output: Contribution to journalArticlepeer-review


Background-11 beta -Hydroxysteroid dehydrogenase (11 beta HSD) isozymes catalyze the interconversion of active and inactive glucocorticoids, allowing local regulation of corticosteroid receptor activation. Both are present in the vessel walls here, using mice with selective inactivation of 11 beta HSD isozymes, we test the hypothesis that 11 beta HSDs influence vascular function.

Methods and Results-Thoracic aortas Were obtained from weight-matched male wild-type (MF1x129 cross(+/+)), 11 beta HSD1(-/-), and 11 beta HSD2(-/-) mice. mRNA for both isozymes was detected in wild-type aortas by RT-PCR. 11 beta HSD activity in aortic homogenates (48.81 +/-4.65% conversion) was reduced in both 11 beta HSD1(-/-) (6.36 +/-2.47% conversion; P <0.0002) and 11 beta HSD2(-/-) (24.71 +/-3.69; P=0.002) mice. Functional responses were unaffected in aortic rings isolated from 11 beta HSD1(-/-) mice. In contrast, aortas from 11 beta HSD2(-/-) mice demonstrated selectively enhanced constriction to norepinephrine (E-max 4.28 +/-0.56 versus 1.72 +/-0.47 mN/mm; P=0.004) attributable to impaired endothelium-derived nitric oxide activity. Relaxation responses to endothelium-dependent and -independent vasodilators were also impaired. To control for chronic renal mineralocorticoid excess, MF1 mice were treated with fludrocortisone (16 weeks) but did not reproduce the functional changes observed in 11 beta HSD2(-/-) mice.

Conclusions-Although both 11 beta HSD isozymes a-re present in the vascular wall, reactivation of glucocorticoids by 11 beta HSD1 does not influence aortic function. Mice with 11 beta HSD2 knockout, however, have endothelial dysfunction causing enhanced norepinephrine-mediated contraction. This appears to be independent of renal sodium retention and may contribute to hypertension in 11 beta HSD2 deficiency.

Original languageEnglish
Pages (from-to)2832-2837
Number of pages6
Issue number23
Publication statusPublished - 4 Dec 2001

Cite this