Published online before print August 18, 2003, doi: 10.1161/01.HYP.0000088855.06598.5B
(Hypertension. 2003;42:580.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
11ß-Hydroxysteroid Dehydrogenase Type 2 in Mouse Aorta
Localization and Influence on Response to Glucocorticoids
From the School of Molecular and Clinical Medicine, Endocrinology Unit, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Correspondence to Dr Patrick W.F. Hadoke, School of Molecular and Clinical Medicine, Endocrinology Unit, 2nd Floor O.P.D., Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, Scotland, UK. E-mail phadoke{at}staffmail.ed.ac.uk
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Abstract |
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Both isozymes of 11ß-hydroxysteroid dehydrogenase, which interconvert active and inactive glucocorticoids, are expressed in the mouse aortic wall. Mice deficient in 11HSD type 2 (which converts active corticosterone into inert 11-dehydrocorticosterone) have hypertension and impaired endothelial nitric oxide activity. It has been suggested that 11HSD2 influences vascular function directly by limiting glucocorticoid-mediated inhibition of endothelium-derived nitric oxide. This study sought to determine (1) the cellular distribution of the 11HSD isozymes within the mouse aortic wall and (2) the influence of 11HSD2 on direct glucocorticoid-mediated changes in aortic function. Mouse aortas were separated into their component layers and RNA extracted for RT-PCR. Both types of corticosteroid (mineralocorticoid and glucocorticoid) receptors and both 11HSD isozymes were expressed in the aortic wall. 11HSD1 expression colocalized with
-smooth muscle actin (a marker for smooth muscle cells), whereas 11HSD2 colocalized with TIE-2 (a marker for endothelial cells). Functional relaxation responses of mouse aortic rings were unaltered after exposure to glucocorticoids for 24 hours. In the presence of L-arginine, glucocorticoids produced an endothelium-independent reduction of contraction; similar results were obtained with aortas from mice with genetic inactivation of 11HSD2. Incubation in medium containing L-arginine reversed the endothelial cell dysfunction associated with 11HSD2 inactivation. Thus, 11HSD2 is appropriately sited to modulate endothelial cell function, but endothelial dysfunction in 11HSD2 knockout mice cannot be explained simply by increased access of corticosterone to endothelial cell corticosteroid receptors. Therefore, additional mechanisms, possibly involving indirect effects of enhanced corticosterone action in the kidney and the resultant hypertension, must be involved.
Key Words: endothelium • glucocorticoids • mice • muscle, smooth, vascular • vasoconstriction • vasorelaxation
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Introduction |
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The access of glucocorticoids to their receptors is regulated by the 11ß-hydroxysteroid dehydrogenase (11HSD) isozymes, which catalyze the interconversion of active glucocorticoids (corticosterone in rodents, cortisol in man) with their inactive metabolites (11-dehydrocorticosterone and cortisone). In most if not all tissues, 11HSD type 1 is a predominant reductase in vivo,1 regenerating active corticosterone from inert 11-dehydrocorticosterone. 11HSD1 is widely expressed and plays an important role in enhancing glucocorticoid receptor (GR) activation in metabolically important sites (eg, liver, adipose tissue). 11HSD type 2 is an exclusive dehydrogenase2 and catalyzes the reverse reaction, inactivating corticosterone. In the adult, 11HSD2 expression is largely restricted to mineralocorticoid target tissues, such as the colon and the distal convoluted tubule of the nephron, where it protects intrinsically nonselective mineralocorticoid receptors (MR) from inappropriate activation by glucocorticoids.3
Both 11HSD isozymes are present in blood vessels, suggesting that concentrations of active glucocorticoid are regulated within the vessel wall. This is important because both GR and MR are present in vascular tissue,4 and glucocorticoids may enhance smooth muscle cell contractility, inhibit endothelium-derived nitric oxide activity, and stimulate vascular hypertrophy.4–6 Indeed, congenital 11HSD2 deficiency, 11HSD inhibition after excessive consumption of liquorice,7,8 and antisense inactivation of 11HSD29 are associated with increased vascular contractility. In aortas from mice homozygous for a disrupted 11HSD2 gene,10 contractility is enhanced as a result of impaired endothelium-derived nitric oxide activity.11 In contrast, genetic inactivation of 11HSD1 has no effect on blood pressure or vascular function in mice.11 Consequently, it was proposed that 11HSD2 expression in endothelial cells influences vascular function by limiting glucocorticoid-mediated inhibition of endothelium-derived nitric oxide activity.
However, there remain uncertainties in this hypothesis. First, the precise cellular distribution of 11HSD isozymes in the vessel wall is uncertain. In cells in primary culture, 11HSD1 and 11HSD2 have been detected in vascular smooth muscle cells,12–14 adventitial fibroblasts, and endothelial cells.12 However, histological studies in rat vessels suggest that immunoreactivity for 11HSD1 is restricted to vascular smooth muscle15,16; data for 11HSD2 are inconsistent, probably on account of the varied characteristics of different antisera.16,17 The inconsistencies in 11HSD isozyme localization in the literature may also be due to differences in expression in arteries from distinct anatomical sites, differences between species, and the use of cultured cells. Studies of liver and adipose cells have indicated that 11HSD isozyme expression is sensitive to culture conditions.18,19 Second, it is not established whether effects of glucocorticoids on vascular function are direct (mediated by either GR or MR) or indirect; it is possible that 11HSD2 manipulations alter other determinants of vascular function or alter vascular structure without increasing activation of corticosteroid receptors in endothelial cells.
In the experiments here, we aimed to clarify the role of 11HSD isozymes in the mouse vessel wall by establishing the cellular distribution of 11HSDs in vivo in cell types of the aortic wall and to determine whether increased exposure (of GR or MR) to glucocorticoid is responsible for endothelial cell dysfunction in the aorta when 11HSD2 is impaired.
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Methods |
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Studies used male MF1 (Harlan Olac) and 11HSD2-/-10 (bred in-house) mice. These were maintained under controlled conditions with free access to standard chow (Special Diet Services) and water. Animals 12 to 16 weeks of age were killed by asphyxiation with CO2: all experiments conformed to standards defined in The Principles of Animal Care (NIH publication No. 85-23, revised 1985).
Drugs
Salts were obtained from BDH; Noradrenaline hydrochloride, 5-hydroxytryptamine creatinine sulfate, and acetylcholine chloride were from Sigma; 3'-morpholinosydnonimine (SIN-1) was from Alexis. Stock solutions (10-3 mol/L) were prepared in distilled water, frozen as 1 mL aliquots at -20°C and thawed as required.
Localization of 11HSD Isozymes in Aortic Wall
Thoracic aorta from MF1 mice were cleaned of fat and connective tissue. Some vessels were rinsed, perfused with collagenase IV (1 to 2 mg/mL, Sigma), and incubated at 37°C with carbogen (5 to 10 minutes) to digest endothelial cells. The medial and adventitial layers were then separated mechanically. Tissues were snap-frozen and stored at -80°C. Frozen tissues were crushed in liquid nitrogen, total RNA was extracted with the use of TRIzol Reagent (Gibco) and quantified by UV spectroscopy.
Total RNA (1 µg) was reverse-transcribed with the use of a Reverse Transcription Kit (Promega) for 45 minutes at 42°C. The resultant cDNA templates underwent PCR amplification (35 cycles) with Taq polymerase (Promega) in the presence of oligonucleotides specific for -smooth muscle actin (-SMA; 5'-TTGGAAAAGATCTGGCACCAC3', and 5'-GCAGTAGTCACGAAGGAATAG-3'), TIE-2 (5'-TTACTCARTACCAGCTCAAGGG-3' and 5'-CAGCTGGTTCTTCTCTCACGTT-3'), 11HSD1 (5'-AAAGCTTGTCACWGGGGCCAGCAAA-3' and 5'-AGGATCCARAGCAAACTTGCTTGC-3'), 11HSD2 (5'-ACCCCTGCTTGGCAGCCTACG GCA-3' and 5'-TCACATTAGTCACTGCCTCTGTCTTG-3'), Glucocorticoid Receptor (5'-TGTGGTTTATAGAGGGCCAAGACTTGG-3' and 5'-GGCACAACTTCCCTTTTCTGATATACAC-3'), and Mineralocorticoid Receptor (5'-CTGAGGAAAATGGTCACCAAGTGTCCCA-3' and 5'-CCACGCCACGTGTTCTGTTATTACATA-3'). Each PCR cycle consisted of denaturation (45 seconds at 95°C), primer annealing (30 seconds at 58°C for -SMA, TIE-2, and 11HSD1; 57°C for corticosteroid receptors; 62°C for 11HSD2), and extension (90 seconds at 72°C), with a final extension period of 10 minutes. RT-PCR products were analyzed by electrophoresis on a 1.8% agarose gel containing ethidium bromide and visualized under UV light. Product sizes for -SMA, TIE-2, GR, MR, 11HSD1, and 11HSD2 were 370 bp, 296 bp, 340 bp, 700 bp, 440 bp, and 144 bp, respectively.
Influence of In Vitro Glucocorticoid Manipulation on Aortic Endothelial Cell Function
Thoracic aortas from MF1 or 11HSD2-/- mice were divided into 3 sections. One section was used immediately for functional investigation; the others were incubated in Dulbecco’s minimum essential medium (DMEM) containing either vehicle, corticosterone (100 nmol/L), or dexamethasone (100 nmol/L). Some experiments used modified DMEM without L-arginine. Incubations were performed at 37°C in an atmosphere of 95% O2/5% CO2 for 24 hours. Each section was then divided into 2 rings and assessed by means of small-vessel myography.11 Cumulative concentration-response curves were obtained for KCl (2.5 to 320 mmol/L) and NE (1 nmol/L to 3 µmol/L). Vasodilator responses were obtained for acetylcholine (ACh; 1 nmol/L to 30 µmol/L) and 3'morpholinosydnonimine (SIN-1; 1 nmol/L to 30 µmol/L) after contraction with 0.1 to 1.0 µmol/L 5-HT. For vessels incubated in the presence of glucocorticoids, functional experiments were performed in the continued presence of the appropriate steroid.
Statistics
Data expressed as mean±SEM and analyzed by means of paired or unpaired Student t test or 2-way ANOVA as appropriate. Differences were considered significant at a level of P<0.05.
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Results |
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Localization of 11HSD Isozymes in Aortic Wall
Vascular Smooth Muscle and Endothelial Cell Marker Expression in Aortic Layers
Expression of
-SMA (the specific marker for vascular smooth muscle cells) was detected in intact aorta and also in isolated medial and adventitial layers (Figure 1a). In contrast, the endothelial cell–specific marker, TIE-2, was detected in endothelium-intact aorta but not in medial or adventitial fractions (Figure 1b). Thus, removal of the endothelium was complete, but RNA could not be successfully extracted from preparations of isolated endothelial cells.
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mRNAs for Corticosteroid Receptors and 11HSD Isozymes in Aortic Layers
GR and MR mRNAs were both detected in mouse aortas (Figures 1c and 1d). Expression of both receptors was also detected in the medial layer after removal of the endothelial and adventitial layers. 11HSD1 mRNA was detected in all samples shown to express -SMA, for example, intact aorta, the isolated medial layer, and the adventitia (Figure 1e). In contrast, expression of 11HSD2 mRNA was only detected in the intact aorta, which was also the only sample to show TIE-2 expression (Figure 1f).
Influence of In Vitro Glucocorticoid Manipulation on Endothelial Cell Function in Mouse Aorta
Preliminary investigations confirmed that contractile and relaxant responses of mouse aortic rings were maintained after incubation in DMEM for 24 hours. After 24-hour incubation, exposure of denuded aortic rings to L-NOARG (10-4 mol/L) had no effect on contractile responses to NE (data not shown), suggesting no significant activation of inducible nitric oxide synthase (iNOS).
MF1 Aortas
In the absence of added L-arginine, incubation with corticosterone had no effect on contractile responses to NE or potassium chloride (Figure 2 and Table 1). In contrast, in the presence of L-arginine (0.85 mmol/L), incubation with corticosterone (100 nmol/L) reduced the amplitude of NE-mediated contraction in denuded aortic rings and in intact rings in the presence of L-NOARG but did not affect NE-mediated contraction of intact aortic rings (Figure 3 and Table 1). The amplitude of potassium chloride–mediated contraction was also attenuated in intact aortic rings incubated with corticosterone; a trend toward reduced contraction did not achieve significance in denuded vessels (Figure 3 and Table 1). The sensitivity of contractile responses was unaffected by exposure to corticosterone.
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) and endothelium-denuded (
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) aortic rings after incubation (24 hours) in L-arginine–free DMEM containing either corticosterone (100 nmol/L; circles) or vehicle (squares). All points represent mean±SEM (n=4 to 8); curves were compared by 2-way ANOVA.
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Incubation with corticosterone had no effect on endothelium-dependent relaxation, either in the presence or absence of L-arginine (Figure 4 and Table 1). Corticosterone had no effect on endothelium-independent relaxation in the presence of L-arginine (Figure 4 and Table 1), but in the absence of L-arginine there was evidence that SIN-1–mediated relaxation was enhanced (Table 1).
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Incubation with dexamethasone (100 nmol/L) in the presence of L-arginine produced effects broadly consistent with those of corticosterone (Table 2). Dexamethasone attenuated NE-mediated contraction in intact as well as in denuded aortic rings and attenuated KCl-mediated contraction in intact but not denuded vessels. Sensitivity to vasoconstrictors and responses to vasodilators were unaffected by dexamethasone.
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11HSD2-/- Aortas
As with wild-type mice, incubation of aortas from 11HSD2-/- mice in the presence of corticosterone had no effect on contractile or relaxant function (Table 3). Furthermore, incubating aortas from these mice in the presence of corticosterone and 0.85 mmol/L L-arginine produced no significant alterations in contractile (Figure 5a and Table 3) or relaxant function; although there was a trend toward enhanced endothelium-independent relaxation (SIN-1) and toward enhanced sensitivity to NE in denuded arteries (Table 3).
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) or after incubation (24 hours) in DMEM with (solid line) or without (dashed line) L-arginine. All points represent mean±SEM (n=4 to 8); curves were compared by 2-way ANOVA; **P<0.00001.As previously reported,11 freshly isolated vessels from 11HSD2-/- mice showed impaired endothelium-dependent vasodilation (Emax, 47.4±10.6%; -logIC50, 6.78±0.11; n=4) and enhanced NE-mediated vasoconstriction (Emax, 2.27±0.40 mN/mm; pD2, 6.73±0.018; n=4). Similar responses were obtained when aortic rings were incubated in DMEM without L-arginine (NE: Emax, 1.70±0.12 mN/mm, P=0.22; pD2, 6.98±0.14, P=0.31; n=4: ACh: Emax, 55.8±3.8, P=0.48; -logIC50, 7.60±0.04, P=0.005; n=4). Incubation of intact aortas from 11HSD2-/- mice in DMEM containing L-arginine for 24 hours resulted in a reduction in the contractile response to NE (Emax; 0.63±0.23 mN/mm; P=0.014; pD2, 7.08±0.01; P=0.10; n=4) (Figure 5b) and an enhancement of acetylcholine-mediated relaxation (Emax, 76.7±3.2%, P=0.023; -logIC50, 7.54±0.27, P=0.04; n=4). In denuded vessels, functional responses of aortas from 11HSD2-/- mice were normal at baseline and unaffected by incubation in DMEM, regardless of the presence of L-arginine (data not shown).
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Discussion |
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The detection of both GR and MR mRNA in mouse aorta and medial smooth muscle, consistent with previous investigations,20 indicates that colocalized 11HSDs may modulate access to either or both receptors. Similarly, the demonstration that both 11HSD1 and 11HSD2 mRNAs are present in mouse aorta is also consistent with previous studies.11 Isolation of the medial layer of the aorta from the endothelium (confirmed by the absence of TIE-2 mRNA expression) allowed the demonstration that 11HSD1 but not 11HSD2 mRNA is expressed in the smooth muscle cells. This is consistent with histological studies15 and studies in vascular smooth muscle cells cultured from rat aorta12 but contrasts with the detection of both 11HSD1 and 11HSD2 mRNA expression in vascular smooth muscle cells cultured from human coronary arteries13 and aorta.14 These differences may reflect the use of smooth muscle from different species and different vascular territories but may also be due to changes in 11HSD isozyme expression resulting from the use of cultured cells. 11HSD1 mRNA detected in mouse aortic adventitial layer subfractions could be attributed to expression either in adventitial smooth muscle cells or fibroblasts.21 Our results have not determined whether 11HSD1 is expressed in mouse aortic endothelial cells. However, immunohistological studies in other species suggest that 11HSD1 is not present in the endothelium of intact arteries.15 In contrast with 11HSD1, 11HSD2 mRNA was only detected in aortic fractions that expressed the marker for endothelial cells (TIE-2). This demonstration of 11HSD2 expression, for the first time in freshly isolated vessels, suggests its localization to be restricted to the endothelium, which supports findings in cultured rat aortic cells.12 These localization studies indicate that 11HSD1 and 11HSD2 are available for intracrine and perhaps paracrine modulation of corticosteroid receptor activation in the vessel wall. Previous studies using knockout mice11 or 11HSD inhibitors7,8,22–24 have suggested that the major influence of 11HSDs on vascular function is determined by dehydrogenase inactivation of glucocorticoids, which is predominantly (if not exclusively25) attributable to 11HSD2.1 Therefore, the influence of endothelial 11HSD2 on vascular responses to corticosterone was explored in greater detail.
The attenuated contraction observed in wild-type mouse aortic rings, after exposure to a physiological concentration of glucocorticoid for 24 hours in vitro, occurred only in the presence of L-arginine but was the result of changes in the vascular smooth muscle. Impaired contractility was evident in denuded aortas and was also unmasked in vessels with an intact endothelium after inhibition of nitric oxide synthase (NOS). Activation of iNOS in the vascular smooth muscle11 did not contribute to the reduction in contraction as nonselective NOS inhibition did not enhance contractile responses in denuded aortic rings; moreover, glucocorticoids have previously been shown to prevent induction of iNOS.26 The fact that both receptor-dependent and receptor-independent vasoconstriction were attenuated suggests that alterations in signaling within the smooth muscle; glucocorticoids can influence G protein–receptor interactions and ion channel activity. Glucocorticoid-mediated alterations in ion transport in the vasculature have been reported, but most studies suggest that these changes would result in enhanced rather than attenuated contractility.27–30 The current findings in mice are consistent with our previous work with rat aorta exposed to glucocorticoids in vitro.8 However, some reports on rat vessels show enhanced contraction attributed to glucocorticoid-mediated inhibition of endothelium-derived nitric oxide,6 an effect that may also be important in human vessels.5 The present results indicate that neither endothelium-dependent nor endothelium-independent relaxation of mouse aortas were altered by exposure to glucocorticoids in vitro. Discrepancies in this literature may relate to differences between species or variable experimental protocols. Investigators have used widely varying steroid concentrations and length of incubation. Moreover, availability of nitric oxide in different preparations may vary; dexamethasone has been shown to inhibit iNOS activity, which is induced in many organ bath experiments26 but was shown not to be relevant in our preparations. Finally, these results suggest that enhanced arterial contraction in response to -adrenoceptor agonists after in vivo exposure to glucocorticoids is not mediated by a direct interaction between the steroid and the cells of the vascular wall.
One interpretation of the current findings is that mouse aortic endothelial cells, which we show here express 11HSD2, are protected from the actions of corticosterone. In the absence of glucocorticoid-induced endothelial dysfunction, attenuated contraction may become apparent. However, similar effects were obtained with the use of dexamethasone, a synthetic steroid that is less susceptible to inactivation by 11HSD231,32 but is a GR rather than mixed MR/GR agonist. This might suggest that the attenuating effects of these steroids on contractile responses are mediated by GR in vascular smooth muscle and that the endothelial effects are MR-mediated; corticosterone might not gain access to MR within endothelial cells because they are protected by 11HSD2. However, to support this attractive hypothesis requires evidence that in the absence of 11HSD2, corticosterone does then induce endothelial dysfunction and hence enhanced contractile responses. In fact, in aortas from 11HSD2 knockout mice, we found that in vitro incubation with corticosterone, even in the absence of L-arginine supplementation, had no effect on endothelial function or contractile responses. Furthermore, with L-arginine incubation in vitro, the endothelial dysfunction in 11HSD2 knockout mouse vessels could be washed out over 24 hours. There are discrepancies between the lack of effect of corticosterone in vitro in vessels from 11HSD2 knockout mice and the potentiation of corticosterone action in vitro previously reported with pharmacological inhibition of 11HSDs in rat vessels.8,22 However, pharmacological inhibitors have nonspecific actions, including toxicity to endothelial cells, which suggest that the present results may more reliably indicate the influence of 11HSD2. We conclude that the endothelial dysfunction in 11HSD2 knockout mice cannot be explained simply by increased access of corticosterone to endothelial cell corticosteroid receptors. Additional mechanisms must come into play, perhaps involving indirect effects of enhanced corticosterone action in the kidney and the resultant hypertension. It is probable that the same caveats will apply to the effects of in vivo pharmacological 11HSD inhibition on vascular function in rats23,24 and humans.7
Perspectives
Our current results suggest that 11HSDs in the vessel wall do not directly modulate corticosterone effects on vascular function. What, then, is the role of these enzymes in vessels? Both the level of mRNA expression and the activity expressed per milligram of protein are low in vessels relative to many other tissues.15 Nonetheless, there are many other important effects of glucocorticoids within the vessel wall, including modulation of vascular development, structure, and inflammatory responses, which may be regulated by 11HSDs. Indeed, these effects may only be apparent in stressed conditions, such as during an inflammatory response, when there is dramatic upregulation of 11HSD1 in particular.14 It appears that more diverse experimental approaches will be required to understand fully the role of 11HSDs in the vessel wall.
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Acknowledgments |
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This research was supported by grants from the Wellcome Trust (including a Cardiovascular Research Initiative PhD studentship) and the British Heart Foundation. J.J. Mullins is the recipient of a Wellcome Trust Principal Research Fellowship. 11HSD1 primers were a gift from Dr Karen Chapman. 11HSD2, GR, and MR primers were a gift from Dr Roger Brown.
Received April 1, 2003; first decision April 17, 2003; accepted July 21, 2003.
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D. X. Zhang, K. M. Gauthier, J. R. Falck, A. Siddam, and W. B. Campbell Steroid-Producing Cells Regulate Arterial Tone of Adrenal Cortical Arteries Endocrinology, August 1, 2007; 148(8): 3569 - 3576. [Abstract] [Full Text] [PDF]
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A. R. Dover, P. W. F. Hadoke, L. J. Macdonald, E. Miller, D. E. Newby, and B. R. Walker Intravascular Glucocorticoid Metabolism during Inflammation and Injury in Mice Endocrinology, January 1, 2007; 148(1): 166 - 172. [Abstract] [Full Text] [PDF]
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 S. K. Paulsen, S. B. Pedersen, J. O. L. Jorgensen, S. Fisker, J. S. Christiansen, A. Flyvbjerg, and B. Richelsen Growth Hormone (GH) Substitution in GH-Deficient Patients Inhibits 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Messenger Ribonucleic Acid Expression in Adipose Tissue J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 1093 - 1098. [Abstract] [Full Text] [PDF]
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 P. J. Fuller and M. J. Young Mechanisms of Mineralocorticoid Action Hypertension, December 1, 2005; 46(6): 1227 - 1235. [Abstract] [Full Text] [PDF]
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 J. M. Paterson, J. R. Seckl, and J. J. Mullins Genetic manipulation of 11{beta}-hydroxysteroid dehydrogenases in mice Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2005; 289(3): R642 - R652. [Abstract] [Full Text] [PDF]
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 G. R. Small, P. W. F. Hadoke, I. Sharif, A. R. Dover, D. Armour, C. J. Kenyon, G. A. Gray, and B. R. Walker Preventing local regeneration of glucocorticoids by 11{beta}-hydroxysteroid dehydrogenase type 1 enhances angiogenesis PNAS, August 23, 2005; 102(34): 12165 - 12170. [Abstract] [Full Text] [PDF]
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 E. E. Kershaw, N. M. Morton, H. Dhillon, L. Ramage, J. R. Seckl, and J. S. Flier Adipocyte-Specific Glucocorticoid Inactivation Protects Against Diet-Induced Obesity Diabetes, April 1, 2005; 54(4): 1023 - 1031. [Abstract] [Full Text] [PDF]
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 I. Z. Jaffe and M. E. Mendelsohn Angiotensin II and Aldosterone Regulate Gene Transcription Via Functional Mineralocortocoid Receptors in Human Coronary Artery Smooth Muscle Cells Circ. Res., April 1, 2005; 96(6): 643 - 650. [Abstract] [Full Text] [PDF]
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 J. R. Seckl, N. M. Morton, K. E. Chapman, and B. R. Walker Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue Recent Prog. Horm. Res., January 1, 2004; 59(1): 359 - 393. [Abstract] [Full Text]
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