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Laboratoire Développement et Vieillissement de l’Endothelium, INSERM EMI 02-19, DRDC/DVE, CEA-Grenoble, 17 rue des Martyrs, 38054 Grenoble, Cedex 9, France
1 INSERM EMI 01-05, Department of Cellular Responses and Dynamics, CEA, Grenoble, France
(Requests for offprints should be addressed to I Vilgrain; Email: ivilgrain{at}cea.fr)
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Abstract |
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 Top Abstract IntroductionMaterials and methodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The steroidogenic adrenal gland is an endocrine tissue characterised by an intense capillary network of highly permeable, often fenestrated vessels that allows the transportation of the endocrine hormones to the blood circulation (Kikuta & Murakami 1982). Adrenal alteration may lead to various disorders such as Addison’s disease, involving an intrinsic alteration of the adrenal gland cortex, or adrenal failure attributable to hypophyseal or hypothalamic pathology (Oelkers et al. 1992, Mayenknecht et al. 1998). The pituitary adrenocorticotrophin hormone (ACTH) is the major trophic factor regulating and maintaining adrenocortical function, affecting such diverse processes as steroidogenesis, cell proliferation, migration, and survival (Gallo-Payet & Payet 2003). Given the variety of the biological events triggered by ACTH, it has been proposed that these effects are induced by multiple relay proteins synthesised and secreted by the steroidogenic cells (Fan & Iseki 1998, Feige et al. 1998). Recent studies have shown that several angiogenic growth factors are produced and secreted by normal endocrine cells and are increased in pathological states of endocrine glands, including inflammation, hyperplasia, and neoplasia (Katoh 2003). Of interest, carcinomas and adenomas in human adrenal cortex differ in their angiogenic patterns as visualised by CD34 labelling (Bernini et al. 2002).
As VE-cadherin is an important determinant of vascular architecture and endothelial survival, we reasoned that this molecule could be regulated during hormonal control of adrenal trophic changes. To investigate this hypothesis, we induced hypothalamo–pituitary axis deficiency in mice by dexamethasone injections (Keller-Wood & Dallman 1984, Dallman et al. 1987). Subsequently, adrenocortical functions were regenerated by ACTH administration. We showed that alteration of adrenal morphogenesis induced by hypothalamo–pituitary axis deficiency was correlated with a decrease in VE-cadherin content. However, endothelial/total cell ratios were maintained during one or both hormone treatments, suggesting that VE-cadherin expression was downregulated in endothelial cells of hypotrophic adrenals. Using VE-cadherin-chloramphenicol acetyl transferase (CAT) transgenic mice, we demonstrated that regulation occurred at the level of transcription. The dexamethasone-induced transcriptional reduction was specific to the adrenal gland, thereby demonstrating that a direct effect of dexamethasone on VE-cadherin promoter could not account for this regulation. After treatment with ACTH, the adrenal regained normal VE-cadherin content. Our results demonstrate that VE-cadherin and thus adrenal endothelial junctions are under the control of pituitary ACTH and our data expand the knowledge regarding the role of ACTH in the regulation of the vascular network in the adrenal gland.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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ACTH(1–39), acetyl-coenzyme A (CoA), benzamidine, dexamethasone, leupeptin, pepstatin A, fluorescein (FITC)-labelled dextran (2 x 106 average molecular weight), Triton X-100 and Tween 20 were purchased from Sigma Chemical Co. (St Louis, MO, USA). Collagenase B, and DNAse I were from Roche (Meylan, France). OCT compound was from Miles Scientific (Elkhart, IN, USA). The metal enhanced diaminobenzidine substrate kit was from Pierce Chemical (Rockford, IL, USA). The enhanced chemiluminescence detection reagents were purchased from Dupont NEN (Les Ulis, France). Nitrocellulose was obtained from Schleicher and Schuell (Ecquevilly, France). The BCA protein assay reagent kit was from Pierce Chemical. [14C]Chloram-phenicol was from Dupont NEN and silica gel plates were from Merck (Darmstadt, Germany).
Antibodies
The rat monoclonal antibody to mouse VE-cadherin (clone 11D4.1) and the isotypic non immune rat IgG2b were from Becton-Dickinson-Pharmingen (San Diego, CA, USA). The CD31 antibody (clone MEC 13.3) was from (Vecchi et al. 1994). Secondary antibodies were from Jackson Immunoresearch Laboratories (West Grove, PA, USA), except the horseradish peroxidase-conjugated goat anti-rat IgG which was from Sigma Chemical.
Animals
All protocols in this study were conducted in strict accordance with the Ministère de l’Education Nationale, de la Recherche et de la Technologie Guidelines for the Care and Use of Laboratory Animals. NMRI mice were purchased from Charles River (Les Oncins, France). The animals were allowed to acclimatise for a period of 1 week before experimental manipulation. VE-cadherin-CAT transgenic mice (Gory et al. 1999) were bred and maintained homozygous in the animal facility.
Dexamethasone and ACTH treatment
Animals were divided into three groups (n=5 per group) with equal average body weight between the three groups. The first group (control, CTL) was treated daily by intraperitoneal (i.p.) injection (200 µl) of sterile 0.9% saline solution for 6 consecutive days. Animals of the second group were treated daily by i.p. injection of dexamethasone (DEX; 5 mg/kg body weight) in 0.9% saline for 6 consecutive days. Animals of the third group received a daily i.p. injection of DEX like the second group and were then treated daily by i.p. injection of ACTH(1–39) (30 IU/kg) for 7 consecutive days. After the treatment, animals were weighed and then killed by i.p. application of an overdose of pentobarbital.
Adrenal histochemistry and morphometry
For immunohistochemistry, adrenal glands were fixed in 4% paraformaldehyde in phosphate buffered saline (PBS) and treated as described in Gaillard et al.(2000). The slides were subsequently incubated with a primary rat monoclonal anti-VE-cadherin antibody (0.5 µg/ml), followed with a biotinylated donkey anti-rat immunoglobulin and horseradish peroxidase-labelled steptavidin. Peroxidase was revealed using the metal enhanced diaminobenzidine substrate kit.
For FITC-dextran labelling, mice were anaesthetised with 100 mg/kg ketamin and 10 mg/kg xylazin and then perfused through the left ventricle with PBS containing 50 µg/ml FITC-dextran. Animals died during perfusion. Immediately after perfusion, adrenals were removed and fixed for 1 h in 4% formaldehyde-PBS at 4 °C. Adrenal glands were then embedded in OCT compound after overnight cryoprotection in 20% (wt/vol) sucrose at 4 °C. Adrenal morphology was analysed as the width of the fasciculata-reticularis zone from FITC-dextran injected mice on adrenal section. Frozen sections (10 µm thick) were mounted in FluorSave and photographed using a fluorescence microscope (Axioplan, Zeiss) equipped with a digital camera (Spot 2, Diagnostic Instruments).
CAT assay
CAT assays were carried out as previously described (Gory et al. 1999). Briefly, mice were killed by CO2 inhalation and the adrenals were carefully dissected from connective tissues. Extracts were prepared by homogenisation using a Polytron in cold PBS and centrifuged for 20 min at 15 000 g. Proteins were added to 100 µl reaction mixture containing 0.25 M Tris–HCl (pH 7.8), 1 mM EDTA, 4.5 µl 100 mM acetyl-CoA and 2.5 µl [14C]chloramphenicol (2.5 Ci/ml). To quantify CAT activity, radioactive spots representing acetylated and nonacetylated forms of chloramphenicol were integrated using a PhosphorImager (Molecular Dynamics, Sunnyvale, CA, USA) and data were expressed as the percentage of acetylated forms over total chloramphenicol.
Western blotting
Adrenals were lysed in lysis buffer, and protein concentration was estimated by the bicinchoninic acid method (Chabre et al. 1995). Proteins (20 µg) from the various adrenocortical extracts were analysed by SDS/PAGE (12% acrylamide). Proteins were then transferred from the gel to nitrocellulose for 1 h and the residual binding sites were blocked by incubating the filters for 1 h in PBS containing 0.05% (v/v) Tween 20 and 5% (w/v) non-fat milk. The blots were subsequently incubated overnight at 4 °C with primary rat mono-clonal anti-VE-cadherin antibody (2 µg/ml in PBS/5% milk/0.05% Tween 20) or with mouse monoclonal anti-ß-tubulin antibody (dilution 1:250 000). After being washed, the blots were incubated for 1 h with horse-radish peroxidase-conjugated rabbit anti-mouse IgG diluted in PBS containing 0.05% (v/v) Tween 20. Immunoreactive proteins were visualised by chemiluminescence (ECL). Signal visualisation was performed by film exposure. The densitometric analysis was performed under the low exposure time of the film.
Flow cytometry analysis
Adrenal glands were dissociated for 1 h at 37 °C with a PBS solution containing 0.2% collagenase B, 200 U/ml DNAse I and 10% fetal calf serum and by repeated flushing through a 21-gauge needle. After two washes in PBS, aliquots containing 1 x 106 cells were incubated for 1 h at 4 °C with 100 µl PBS containing 2% bovine serum albumin, followed by incubation with a rat monoclonal anti-mouse CD31 antibody. After two washes in PBS, the cells were incubated at 4 °C for 1 h with 100 µl PBS containing 2% bovine serum albumin and 13 µg/ml FITC-conjugated (Fab')2 fragments of goat anti-rat IgG. Isotypic non immune rat IgG2b (10 µg/ml) was used as a negative control. The stained cells were washed twice, resuspended in PBS and analysed in a FACScaliber flow cytometer (Becton Dickinson).
Data presentation and statistical analyses
The data are presented as the mean ± S.E.M., and the numbers of subjects in each experimental group are indicated in the figure legends. Significant changes in hormone concentration, adrenal weight and CAT activity were determined by a one-way ANOVA followed by Tukey–Kramer multiple comparisons test.
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Results |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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The vasculature of the adrenal gland was examined by systemic injection of fluorescein isothiocyanate (FITC)-dextran in mouse heart. As shown in Fig. 1A
, the cortical capillaries arise directly from the capsule, initially forming an anastomotic network lining the cells of the zona glomerulosa, then continuing as longitudinal sinusoids running radially between columns of cells within the zona fasciculata.
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). There is a direct continuity between cortical and medullary capillaries. Thus, VE-cadherin expression pattern in the adrenal paralleled the vascular network revealed by FITC-dextran labelling, indicating that VE-cadherin represents a uniform marker of adrenal vasculature.
The presence of VE-cadherin was confirmed by immunoblotting analysis of adrenal extract. Total adrenal proteins (40 µg) were analysed by SDS-PAGE. As shown in Fig. 1C, the antibody recognised a band of appropriate molecular mass of 125 kDa corresponding to VE-cadherin. Equivalent amounts of VE-cadherin were detected in right and left adrenals.
Variation of VE-cadherin expression in response to hormonal treatment
To examine further the role of ACTH on VE-cadherin expression, hypothalamo–pituitary deficiency was induced in mice by dexamethasone administration. Daily i.p. injection of DEX (5 mg/kg body weight) for 6 days induced a significant decrease (P < 0.001) in adrenal weights from 6.3 ± 0.5 mg on day 1 to 3.4 ± 0.2 mg on day 6. The concentration of circulating corticosterone was decreased by 50% (data not shown). On day 6 of DEX administration, mice were injected with FITC-dextran, and adrenals from perfused mice were analysed by fluorescence microscopy. Figure 2A shows a composite fluorescent micrograph of median sections of the adrenals from treated (DEX) or untreated (CTL) mice. A specific decrease in the widths of zonae fasciculata and reticularis was observed associated with a disorganisation of the longitudinal vascular network (Fig. 2B).
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, the intensity of the VE-cadherin band was significantly decreased in DEX-treated adrenals (middle lane), as compared with non-treated adrenals (left lane). After ACTH administration, the amounts of VE-cadherin were comparable to controls (right lane). This pattern of expression was similar in all tested animals (n=10 for each condition). The same blot was also probed with an anti-ß-tubulin antibody as a loading control showing similar levels of protein (Fig. 2C). Densitometric analysis of the signals (n=7 adrenals) confirmed that the relative ratio of VE-cadherin was dramatically decreased (23.5 ± 3.7%) after steroid treatment of mice (Fig. 2D) and restored after secondary treatment with ACTH (94.9 ± 18.6%). We thus conclude that the morphological changes observed in adrenals after dexamethasone treatment are correlated with the dramatic reduction in VE-cadherin. Endothelial cell analysis by flow cytometry
To determine whether the observed variations of VE-cadherin were caused by a modification of the endothelial versus total cell ratio, we performed flow cytometry analyses of adrenal cells from treated and untreated mice after collagenase dissociation and CD31 labelling. CD31 is a uniform marker of endothelial cells, resistant to collagenase treatment (DeLisser et al. 1994). The percentage of endothelial cells was obtained using light scatter and fluorescence characteristics. In untreated (CTL) adrenals, antibodies to CD31 recognised a distinct sub-population (Fig. 3A, CTL, right panel), whereas cells incubated with non immune rat immunoglobulins harboured background staining (Neg). The percentages of CD31-positive cells in adrenal tissues were highly reproducible; variations were found to be less than 5% of the mean when three independent measurements were performed on one adrenal. Representative examples of flow cytometry analyses of cells from untreated, DEX- or DEX/ACTH-treated adrenals are shown in Fig. 3A. Mean percentages of CD31-positive cells (Fig. 3B) were remarkably stable after one or both hormone treatments: CTL, 35.11 ± 2.77%; DEX, 34.8 ± 3.7%; DEX/ACTH, 35.77 ± 4.8% (n=10 independent glands in each group). These data show that ACTH coordinately regulates the extent of the steroidogenic and vascular systems in the adrenal cortex. Furthermore, this experiment allowed us to conclude that changes in VE-cadherin levels observed after dexamethasone treatment did not result from variable proportions of endothelial cells in adrenals during regression-regeneration experiments. Rather, these data suggest that VE-cadherin expression was decreased in endothelial cells after dexamethasone administration.
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To analyse whether the decrease in VE-cadherin expression was caused by a transcriptional inhibition of the VE-cadherin gene, we used transgenic mice carrying the CAT gene under the control of the VE-cadherin promoter (Gory et al. 1999). Measurement of CAT enzymatic activity in organ extracts from these mice is a precise and very sensitive way to quantify VE-cadherin promoter activity and to evaluate its regulation.
Although the transgene was previously shown to be expressed in a number of organs, expression in adrenals had never been examined. Thus, protein extracts from adrenal glands were prepared and assayed for CAT enzymatic activity. Figure 4A shows that CAT activity was detectable in adrenal extract from 1 to 20 µg. As illustrated in Fig. 4B, the reaction was linear from 2 to 10 µg after 120 min of incubation. The time course of CAT activity using 10 µg protein revealed a linear reaction that was detectable after 10 min of incubation and was linear up to 120 min (Fig. 4C). Enzyme activity was assayed in the right and left adrenals of the same animals and, at each tested time of incubation, the same levels were obtained for 2, 5, or 10 µg protein (data not shown). Lung and liver were used as control organs and tested in the same enzymatic kinetic analyses. As shown in Fig. 4D, we found that CAT activities of individual organs from different mice (n=12) were repeatedly similar: lung 65.0 ± 5.0%, adrenal 29.8 ± 4.2%, liver 3.1 ± 0.4% of conversion/10 µg/30 min, indicating that comparison of CAT activity is possible between mice receiving different treatments.
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Transgenic mice received one or both hormone treatments and CAT activity was analysed in the adrenal, lung and liver in each group. In the following experiments, CAT activities were determined in linear conditions (120-min incubation), using 2 µg extracts from eight adrenals (four mice) in each group. As illustrated in Fig. 5, CAT activity in the adrenal gland of the DEX group was significantly decreased (40%; P < 0.05) as compared with the CTL group (100%). Treatment of transgenic mice with ACTH for 7 days restored the CAT activity of the DEX group, almost to the control level (82%). As the observed decrease in CAT activity in the adrenals may be caused by a direct effect of dexamethasone on VE-cadherin promoter, we determined transgene expression in lung and liver, two organs that are not regulated by ACTH. As shown in Fig. 5, no significant variation in CAT activities could be measured in lungs and livers from each group. These data indicate that a direct effect of dexamethasone on VE-cadherin promoter activity could not account for the observed decrease in the adrenals. Altogether, our results show that VE-cadherin expression in adrenal vessels is controlled at the transcriptional level by hypothalamus–pituitary inputs.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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In the adrenal gland, our results demonstrate that VE-cadherin expression is regulated by ACTH. The hormone action depends on the expression of its specific receptors. To date, five melanocortin (MC) receptors have been identified and shown to have a wide distribution throughout the body and probably many diverse functions (Magenis et al. 1994). ACTH preferentially binds to the MC2 receptor (Hofmann et al. 1988, Mizuno et al. 1989, Penhoat et al. 1993), hence it is considered to be the main ACTH receptor. MC2 receptor is mainly expressed in the zona fasciculata (the site of glucocorticoid production) and in zona glomerulosa (the site for mineralocorticoid production) in the adrenal cortex (Mountjoy et al. 1992, Xia & Wikberg 1996, Reincke et al. 1998). To our knowledge, no MC2 receptor has been identified in adrenal endothelial cells or in other types of endothelium. Furthermore, treatment of human umbilical vein endothelial cells with ACTH or dexamethasone did not alter VE-cadherin mRNA content in these cells (data not shown). It is thus likely that VE-cadherin regulation in the adrenal is mediated by steroidogenic cells, through an indirect effect of the hormone. Indeed, ACTH was described to induce the expression of several growth factors and proteins of the extracellular matrix in cultured adrenocortical cells (Feige et al. 1998). However, future studies are necessary to get further insights into the molecular mechanisms regulating adrenal VE-cadherin expression.
Our flow cytometry analysis of adrenal cells indicates that the hormonal treatment did not modify the ratio of endothelial over total adrenal cells. This feature suggests that the observed modifications in VE-cadherin content were not caused by a variation of the endothelial/adrenal cell ratio. To examine whether this regulation occurred at the transcriptional level, we used VE-cadherin-CAT transgenic mice to monitor VE-cadherin gene regulation (Gory et al. 1999). Measurement of CAT activity in several tissues proved to be a very sensitive and reproducible test to monitor VE-cadherin promoter activity. This assay is specific to transcriptional activity, independent of potential VE-cadherin post-transcriptional regulation such as mRNA stabilization. CAT activity was highly detectable in the adrenal of adult transgenic mice. We demonstrated the existence of regulation of VE-cadherin promoter in treated adrenals. In contrast, in lung and liver, two organs that are not regulated by the hypothalamo–pituitary axis., no modification in VE-cadherin promoter activity was detected, which is in agreement with the tissue specificity of ACTH action. These data further demonstrate that the VE-cadherin promoter is not under direct glucocorticoid regulation. Our data are consistent with a model where glucocorticoids and ACTH are not independent regulators of VE-cadherin promoter. We speculate that the level of mouse ACTH is the only important parameter in this process. Previous studies showed that tumour necrosis factor-alpha could also downregulate VE-cadherin transcription in cultured endothelial cells (Hofmann et al. 2002). Altogether, these findings suggest that VE-cadherin is subjected to regulation in response to various physiological stimuli.
Although mechanisms underlying adrenal capillary regulation have not been clearly elucidated, data from several investigations demonstrated that steroidogenic adrenal cells release angiogenic factors (Feige et al. 1998, Gaillard et al. 1999), such as the VEGF, the angiopoietins, and their cognate receptors VEGF R1, VEGF R2 and Tie 2 (Vittet et al. 2000, Feraud et al. 2003). More recently, a human endocrine gland-derived vascular endothelial growth factor (EG-VEGF) was described as an endothelial cell mitogen with a selective activity on steroidogenic gland endothelial cells (LeCouter & Ferrara 2003). However, the study of the coordinated interactions and the identity of the soluble factors involved in vivo has been very difficult. A cross-talk between VEGF R2 and VE-cadherin was previously shown to stimulate endothelial cell survival by the phosphorylation of Akt (phospho-kinase B) and the induction of BclII (Carmeliet et al. 1999). VE-cadherin deficiency increased endothelial apoptosis and abolished transmission of the survival signal induced by VEGF-A through reduced complex formation between VEGF-R2, beta-catenin, and phosphatidylinositol 3-kinase (Carmeliet et al. 1999). Thus, it is likely that a coordinated regulation of both proteins might be at the origin of the vascular regulation accompanying the structural modifications of the adrenal gland.
In conclusion, these findings indicate that VE-cadherin expression is regulated during vascular reorganisation triggered by physiological agonists. Given that VE-cadherin is involved in vascular morphogenesis and endothelial survival, the fact that its expression is regulated by hormonal treatment strongly suggests that VE-cadherin may be a key player in the coordination of vascular and steroidogenic systems.
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Acknowledgements |
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References |
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Received 22 September 2004
Accepted 12 October 2004
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