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(Circulation. 2001;104:2832.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Endothelial Cell Dysfunction in Mice After Transgenic Knockout of Type 2, but Not Type 1, 11ß-Hydroxysteroid Dehydrogenase

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

From the Endocrinology (P.W.F.H., C.C., B.C.W., C.J.K., J.R.S., B.R.W.), Endothelial Cell Biology (Y.V.K.), and Molecular Physiology (J.J.M.) groups, University of Edinburgh, Edinburgh, UK.

Correspondence to Dr Patrick Hadoke, Endocrinology Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. E-mail phadoke{at}srv0.med.ed.ac.uk

Background— 11ß-Hydroxysteroid dehydrogenase (11ßHSD) 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 11ßHSD isozymes, we test the hypothesis that 11ßHSDs influence vascular function.

Methods and Results— Thoracic aortas were obtained from weight-matched male wild-type (MF1x129 cross^+/+), 11ßHSD1^-/-, and 11ßHSD2^-/- mice. mRNA for both isozymes was detected in wild-type aortas by RT-PCR. 11ßHSD activity in aortic homogenates (48.81±4.65% conversion) was reduced in both 11ßHSD1^-/- (6.36±2.47% conversion; P<0.0002) and 11ßHSD2^-/- (24.71±3.69; P=0.002) mice. Functional responses were unaffected in aortic rings isolated from 11ßHSD1^-/- mice. In contrast, aortas from 11ßHSD2^-/- 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 11ßHSD2^-/- mice.

Conclusions— Although both 11ßHSD isozymes are present in the vascular wall, reactivation of glucocorticoids by 11ßHSD1 does not influence aortic function. Mice with 11ßHSD2 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 11ßHSD2 deficiency.

Key Words: hydroxysteroid dehydrogenases • hypertension • aorta • endothelium • vasoconstriction

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