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

Patrick W.F. Hadoke, Clare Christy, Yuri V. Kotelevtsev, Brent C. Williams, Christopher J. Kenyon, Jonathan R. Seckl, John J. Mullins, Brian R. Walker

Research output: Contribution to journalArticlepeer-review

68 Citations (Scopus)

Abstract

Background - 11β-Hydroxysteroid dehydrogenase (11βHSD) isozymes catalyze the interconversion of active and inactive glucocorticoids, allowing local regulation of corticosteroid receptor activation. Both are present in the vessel wall; here, using mice with selective inactivation of 11βHSD isozymes, we test the hypothesis that 11βHSDs influence vascular function. Methods and Results - Thoracic aortas were obtained from weight-matched male wild-type (MF1×129 cross+/+), 11βHSD1-/-, and 11βHSD2-/- mice. mRNA for both isozymes was detected in wild-type aortas by RT-PCR. 11βHSD activity in aortic homogenates (48.81±4.65% conversion) was reduced in both 11βHSD1-/- (6.36±2.47% conversion; P<0.0002) and 11βHSD2-/- (24.71±3.69; P=0.002) mice. Functional responses were unaffected in aortic rings isolated from 11βHSD1-/- mice. In contrast, aortas from 11βHSD2-/- mice demonstrated selectively enhanced constriction to norepinephrine (Emax 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 11βHSD2-/- mice. Conclusions - Although both 11βHSD isozymes are present in the vascular wall, reactivation of glucocorticoids by 11βHSD1 does not influence aortic function. Mice with 11βHSD2 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 11βHSD2 deficiency.

Original languageEnglish
Pages (from-to)2832-2837
Number of pages6
JournalCirculation
Volume104
Issue number23
DOIs
Publication statusPublished - 4 Dec 2001
Externally publishedYes

Keywords

  • Aorta
  • Endothelium
  • Hydroxysteroid dehydrogenases
  • Hypertension
  • Vasoconstriction

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