| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLES |
Department of Physiological Sciences, Eastern Virginia Medical School (G.J.P., M.G.B.), Norfolk, Virginia 23507; and Departments of Obstetrics/Gynecology/Reproductive Sciences and Physiology, Center for Studies in Reproduction, University of Maryland School of Medicine (E.D.A.), Baltimore, Maryland 21201
Address all correspondence and requests for reprints to: Gerald J. Pepe, Ph.D., Department of Physiological Sciences, Eastern Virginia Medical School, P.O. Box 1980, Norfolk, Virginia 23501-1980. E-mail: pepegj{at}evms.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
It is well known that 11ßHSD-1 can function as a reductase, whereas 11ßHSD-2 only catalyzes the oxidation of cortisol to cortisone. Therefore, because the levels of both 11ßHSD enzymes were comparably increased in the syncytiotrophoblast with advancing gestation, we (8) concluded that the estrogen-induced change in the pattern of transplacental cortisol-cortisone metabolism from reduction at mid-gestation to oxidation near term is not simply the result of a change in the relative concentrations of these two enzymes. Rather, we propose that these two enzymes reside in different locations within the developing syncytiotrophoblast and that there is a developmental change in their localization that dictates the qualitative pattern of cortisol and cortisone crossing the syncytiotrophoblast into the fetus. Indeed, the syncytiotrophoblast is polarized, and such enzymes, including alkaline phosphatase and sodium-potassium adenosine triphosphatase, are localized specifically to the microvillus and basal membranes, respectively (11).
Therefore, the current study was designed to determine whether 11ßHSD-1 and -2 are located in different compartments of the baboon and human syncytiotrophoblast and whether there is a developmental change in their localization with advancing gestation. To examine these possibilities, we compared the levels of 11ßHSD-1 and -2 protein by Western blot in enriched fractions of the syncytiotrophoblast and their localization in the syncytiotrophoblast by immunofluorescence and electron microscopic (EM) immunocytochemistry in the baboon placenta obtained at mid- and late gestation and human placenta at term.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Western blot analyses
Western blot analysis of 11ßHSD-1 and -2 in homogenates of
whole villous placenta as well as in various membrane fractions,
including the MVM, endoplasmic reticulum/cytosol, and the
BMm, was performed essentially as described
previously (8, 9). Briefly, membrane fractions were
solubilized in 1.0% Triton X-100 (Sigma), 250
mM sodium chloride (Sigma), 25 mM
Tris-HCl (pH 7.5; Bio-Rad Laboratories, Inc. Richmond,
CA), 5 mM EDTA (pH 8.0; Sigma), 1
mM phenylmethylsulfonylfluoride (Sigma), 2
µg/ml aprotinin (Sigma), 2 µg/ml pepstatin A
(Sigma), and 10 µg/ml leupeptin (Sigma) and
incubated on ice for 20 min. Samples of whole villous tissue from
baboon and human placentas were suspended in 1% cholic acid
(Sigma), 0.1% SDS (Sigma), and 1 mm EDTA in
PBS (pH 7.4) containing 0.1 mg/ml phenylmethylsulfonylfluoride, 10
µg/ml aprotinin, and 0.1 mg/ml soybean inhibitor (Sigma)
and homogenized on ice with a Polytron (Brinkmann Instruments, Inc., Westbury, NY). After determination of protein
concentration by the bicinchoninic acid procedure (Sigma),
5 x Laemmli buffer was added to a final concentration of 1
x (13), and all samples were heated at 100 C for 5 min,
cooled on ice for 2 min, and loaded (30 µg protein/lane) onto
discontinuous SDS-polyacrylamide minigels (12% for 11ßHSD-1; 10%
for 11ßHSD-2) maintained in Bio-Rad Laboratories, Inc.,
Mini-Protean II electrophoresis chambers (Bio-Rad Laboratories, Inc.) containing chilled 0.025 M Tris, 0.192
M glycine (Bio-Rad Laboratories, Inc.), and
0.1% SDS buffer (pH 8.3). Samples were electrophoresed and wet
transferred to Immobilon P (Millipore Corp., Bedford, MA)
with a Mini Trans Blot transfer unit. The membrane was then blocked
after incubation with constant agitation for 1 h at 37 C in 3%
BSA in 50 mM Tris, pH 7.5, containing 150 mm NaCl and
0.05% Tween-20 (Bio-Rad Laboratories, Inc.). Samples were
incubated (1 h) at room temperature with polyclonal antibodies to
11ßHSD-1 and -2, which were prepared (Cocalico Biologicals,
Reamstown, PA) from rabbits injected with multiple antigenic peptides
composed of an eight-branched lysine core matrix to which amino acids
22–36 of human 11ßHSD-1 and 332–345 of human 11ßHSD-2 were
coupled as described previously (9). Both antibodies were
partially purified using a Protein A Plus column (Pierce Chemical Co., Rockford, IL) and dialyzed against PBS. The specificity and
applicability of these antibodies for analysis of 11ßHSD-1 and -2 in
baboon and human placenta were described previously (9).
Primary antibodies were diluted to 10 µg/ml in buffer I [50 mm Tris
(pH 7.5), 150 mm NaCl, 0.05% Tween-20, and 0.05% IGEPAL CA-630]
containing 1.5% BSA. Membranes were washed and incubated at room
temperature for 1 h with donkey antirabbit IgG horseradish
peroxidase-conjugated second antibody (Amersham Pharmacia Biotech, Arlington Heights, IL) at the dilutions recommended by
the manufacturer in buffer I containing 1.5% BSA. After washing, equal
amounts of enhanced chemiluminescent reagent (ECL, Amersham Pharmacia Biotech) were applied to membranes for 1 min.
Membranes were then wrapped in plastic, placed in x-ray film cassettes
containing Fugi Medical x-ray film (Fugi
Medical Systems, Stamford, CT), and exposed in a dark room for 15–180
sec. Preliminary studies confirmed that the second antibody contributed
no nonspecific bands at the concentrations employed. To compare the
levels of 11ßHSD-1 and -2 in whole villous homogenate, the MVM or the
BMm between mid-and late gestation, Western blots
were developed in the same film cassette for both 11ßHSD-1 and -2.
After film development, samples were quantified by one-dimensional
densitometry using an Image 1 analysis system (Universal Imaging Corp.,
Reamstown, PA), and results were expressed as arbitrary densitometric
units per µg protein, per mg tissue, or per placenta
(8).
Immunofluorescence
Sections (4 µm) of formalin-fixed, paraffin-embedded baboon
placenta were mounted onto SuperFrost Plus microscope slides
(Fisher Scientific, Philadelphia, PA), and endogenous
peroxidase was blocked with 0.4% hydrogen peroxide in methanol. Slides
were placed in 10 mM sodium citrate buffer (pH 6.0;
Sigma) and microwaved for 15 min. After cooling (30 min),
sections were washed in PBS, blocked (30 min) in 5% normal goat serum
(NGS; Vector Laboratories, Inc., Burlingame, CA), and then
incubated overnight at 4 C with primary antibodies to 11ßHSD-1 and -2
diluted 1:2000 in 5% NGS. Sections were washed and incubated for
2 h at room temperature with biotinylated antirabbit IgG
(Zymed Laboratories, Inc., South San Francisco, CA)
diluted 1:500 in 5% NGS. Biotin was detected after treatment for 30
min in the dark with streptavidin conjugated with a Cy3 fluorotag
(Zymed Laboratories, Inc.) diluted 1:50 in 5% NGS. Slides
were rinsed in PBS, and autofluorescence was quenched by incubation (10
min) in the dark with Sudan Black (Sigma; 1% in 70%
methanol). Sections were then rinsed in PBS, and coverslips were
mounted using Vectashield mounting medium for fluorescence
(Fisher Scientific) and secured using rubber cement.
Slides were stored at 4 C in the dark until being photographed with
Elite Chrome 400-color film (Eastman Kodak Co., Rochester,
NY) using a Nikon FX-35 WA camera and Nikon
MICROPHOT-FX microscope and rhodamine filter (Nikon,
Melville, NY).
EM immunocytochemistry
EM immunocytochemistry was also used to confirm the
intracellular localization of 11ßHSD-1 and -2 within the baboon
syncytiotrophoblast at mid- and late gestation using primary antibodies
to 11ßHSD-1 and -2 that were partially purified by ammonium sulfate
precipitation. Sections of placental villous tissue were fixed
overnight in Zamboni’s solution and embedded in capsules containing LR
White Resin (Fisher Scientific). Ultrathin sections were
collected onto 200-mesh nickel grids and after blocking were incubated
overnight (4 C) with or without primary antibodies to 11ßHSD-1 or -2.
After several washes in Tris-buffered saline, sections were incubated
at room temperature for 60 min with goat antirabbit secondary
antibody-coated colloidal gold (18 nm), washed, counterstained with 2%
aqueous uranyl acetate, and examined by transmission EM.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
illustrates a
representative EM photomicrograph of the intact near-term baboon
placental syncytiotrophoblast and its component nuclei and cellular
organelles, a MVM facing the maternal side, and a BM facing the fetal
vasculature. As shown in Fig. 1B, the MVM was totally removed by
mechanical agitation in PBS, and as a consequence a portion of the
cytosolic contents was extruded along with the MVM. However, the
membranes contiguous with the BM (i.e. not contiguous with
the MVM) and those cytosolic organelles of the syncytiotrophoblast not
lost after mechanical agitation remained intact. Based on alkaline
phosphatase activity, the MVM obtained by mechanical agitation was
enriched at both mid- and late gestation approximately 16- to 20-fold
by high speed centrifugation in mannitol and
MgCl2 (Table 1).
Because the fraction of the filtrate obtained by centrifugation at
10,000 x g was also enriched for alkaline phosphatase
activity by approximately 3-fold, it appears that the 10,000 x
g fraction also contained some MVM.
|
|
, the contents of the syncytiotrophoblast,
including BMm, were released by sonication.
However, the BM remained intact and was only released after a second
sonication (data not shown). Alkaline phosphatase activity was minimal
in BMm and BM (Table 1). The specific activity of
alkaline phosphatase in whole villous homogenate and MVM was
approximately 3-fold greater at late gestation than at midgestation
(Table 1). As shown in Table 2, the
concentration of soluble protein in whole villous placental homogenate
was approximately 40% greater (P < 0.05) near term
than at midgestation. Of the three trophoblast fractions examined,
protein concentrations were greatest in BMm.
However, protein concentrations in MVM, but not the
BMm or 10,000 x g
fraction, appeared to be 2- to 3-fold greater (P
= 0.08) near term than at midgestation.
|
depicts representative
Western blots for 11ßHSD-1 and -2 expression in homogenate of whole
villous placenta and in MVM, the cytosolic contents released after
mechanical agitation of the syncytiotrophoblast (i.e. the
10,000 x g fraction), as well as the
BMm released by sonication of the
syncytiotrophoblast of baboon placenta obtained at mid- and late
gestation and the human placenta collected at term. As previously
demonstrated, in baboon and human placental syncytiotrophoblast
(9), 11ßHSD-1 was expressed as a 32-kDa protein, and
11ßHSD-2 was expressed as a doublet of approximately 40 and 42 kDa.
Specificity was confirmed by demonstration of the absence of the 32-kDa
11ßHSD-1 and 40- to 42-kDa 11ßHSD-2 signals using antibodies
preabsorbed with an excess of the respective immunizing peptide (Fig. 2D). In both the human and the baboon, 11ßHSD-1 expression was most
extensive in the MVM, relatively lower in the 10,000 x
g fraction, and lower, but still detectable, in the
BMm. Moreover, in the baboon, although the level
of 11ßHSD-1 in the MVM was similar or slightly greater at term than
at midgestation, 11ßHSD-1 expression in the BMm
decreased with advancing gestation (Fig. 2). In contrast to these
observations, in both the human and the baboon, 11ßHSD-2 was
expressed in low abundance in the MVM and was present in
relatively high levels in both the 10,000 x g fraction
and the BMm. Moreover, in the baboon, levels of
11ßHSD-2 in the 10,000 x g fraction and the
BMm were similar at both mid- and late gestation.
Based on location in the gel, it would appear that sonication of the
BMm modified the 11ßHSD-2 protein. Thus, the
mobility of 11ßHSD-2 in the 10,000 x g fraction was
comparably reduced after sonication (data not shown).
|
, 11ßHSD-1 was
detected by immunofluorescence in the MVM and contiguous regions of the
syncytiotrophoblast and occasionally in fetal vascular cells, but not
in syncytiotrophoblast nuclei, at both mid (Fig. 3A) and late (Fig. 3B)
gestation. Although 11ßHSD-1 was also detected in regions of the
syncytiotrophoblast contiguous with and/or in proximity to the BM at
midgestation (Fig. 3A), expression of 11ßHSD-1 in this region of the
syncytiotrophoblast juxta the inner villous core was considerably
reduced in late gestation (Fig. 3B). Similar results were observed
using EM immunocytochemistry (Fig. 4).
Thus, gold particles reflective of 11ßHSD-1 expression were detected
in the MVM and contiguous regions of the syncytiotrophoblast at both
mid (Fig. 4A) and late (Fig. 4B) gestation. However, whereas gold
particles reflective of 11ßHSD-1 were noted in the BM region of the
syncytiotrophoblast at midgestation (Fig. 4A), gold particles
associated with 11ßHSD-1 became less abundant in regions close to
fetal blood (i.e. inner villous core) in late gestation
(Fig. 4B). The specificity of these immunocytochemistry studies was
confirmed by the absence of fluorescence and gold particles in sections
of mid (Figs. 3E and 4C, respectively) and late (not shown) gestation
baboon placenta incubated without primary antibody to 11ßHSD-1 and by
the paucity of grains over nontissue areas in sections incubated with
primary antibody (Fig. 4, A and B).
|
|
) and late (Fig. 3D)
gestation, 11ßHSD-2 was detected by immunofluorescence throughout the
syncytiotrophoblast, including regions close to the inner villous core,
but was not expressed in the MVM. The protein for 11ßHSD-2 was also
detected in and/or associated with the syncytiotrophoblast nuclei and
was occasionally detected in vascular cells in the inner villous core.
Consistent with these immunofluorescence data, EM immunocytochemistry
showed that gold particles reflective of 11ßHSD-2 expression were
uniformly distributed at mid (Fig. 5A)
and late (Fig. 5B) gestation throughout the syncytiotrophoblast,
including regions contiguous with the BM (i.e.
BMm) as well as the BM itself, but were much less
abundant in the MVM. Grains reflective of 11ßHSD-2 expression were
also observed over syncytiotrophoblast nuclei and appeared to be
associated mostly with the heterochromatin (not shown). Specificity was
confirmed by the absence of fluorescence and gold particles in sections
of mid (Figs. 3E and 5C, respectively) and late (not shown) gestation
incubated without primary antibody to 11ßHSD-2 and by the paucity of
grains over nontissue areas in sections incubated with primary antibody
(Fig. 5C).
|
). However, because
the volume fraction of the chorionic villi occupied by capillaries and
extratrophoblastic components increases with advancing gestation,
whereas the volume fraction of trophoblast remains relatively constant,
and 11ßHSD is only expressed in the syncytiotrophoblast (8, 9), the specific activity (e.g. per µg protein) of
11ßHSD-2 was similar at mid- and late gestation (Fig. 6A). Consistent
with these observations, the results of the current study show that
although the concentration of 11ßHSD-2 protein (arbitrary
densitometric units) per µg whole villous protein (Fig. 6C) or per mg
tissue (not shown) was similar at mid (58,147 ± 1,738) and late
(48,023 ± 3,769) gestation, total placental expression of
11ßHSD-2 protein (i.e. the product of 11ßHSD-2 and
placental weight; units x
10-9/placenta) was 3-fold
greater (P = 0.05) on day 180 (29.9 ± 6.1) than
on day 100 (11.3 ± 2.8; Fig. 6D). Similar observations were noted
for 11ßHSD-1 protein concentrations (Fig. 6E) and levels per placenta
(Fig. 6F). Thus, in whole villous baboon placenta, as previously shown
for 11ßHSD-1 and -2 mRNA and protein levels in syncytiotrophoblast,
the expression of both proteins increases with advancing gestation
apparently at comparable rates, as indicated by the similarity in the
ratio of 11ßHSD-2 to 11ßHSD-1 in whole villous homogenate at mid
(2.0 ± 0.2) and late (1.9 ± 0.2) gestation (Fig. 6G).
Therefore, the similar increases in 11ßHSD-1 and -2 in whole villous
placenta cannot account for the transplacental switch in conversion of
bioactive cortisol to bioinactive cortisone between mid- and late
gestation.
|
, the mean
(±SE) concentrations (arbitrary densitometric units per
µg protein) of 11ßHSD-1 protein in the MVM were similar at mid
(38,859 ± 3,484) and late (43,561 ± 1,784) gestation and
greatly exceeded (P < 0.01) respective values for
11ßHSD-2 by approximately 16-fold (Fig. 7A). When values were
corrected for the total amount of protein associated with the MVM and
expressed as total 11ßHSD-1 in the MVM (arbitrary densitometric
units x
10-6/placenta; Fig. 7B),
11ßHSD-1 in the MVM was approximately 6-fold greater
(P = 0.07) in late gestation (101 ± 32) than at
midgestation (17 ± 10). Again, however, the ratio of 11ßHSD-2
to 11ßHSD-1 in the MVM (Fig. 7C) was similar at mid (0.06 ±
0.04) and late (0.06 ± 0.01) gestation, and therefore, levels of
these enzymes in the MVM also cannot explain the switch in
transplacental cortisol-cortisone metabolism with advancing
gestation.
|
) gestation, and thus the total amount
(units x
10-6/placenta) of
11ßHSD-1 in the BMm did not change with
advancing gestation (Fig. 8B). However, the concentration (units per
µg protein) of 11ßHSD-2 in the BMm increased
(Fig. 8A), although not significantly, between mid (8,506 ± 850)
and late (10,624 ± 3,194) gestation, and thus the total amount of
11ßHSD-2 in the BMm (units x
10-6/placenta) was
approximately 2-fold greater at term (835 ± 322) than at
midgestation (383 ± 97; Fig. 8B). Because of these changes, the
ratio of 11ßHSD-2 to 11ßHSD-1 in the BMm of
the syncytiotrophoblast at midgestation (1.22 ± 0.10) was
increased (P < 0.05) by approximately 2-fold in late
gestation (2.66 ± 0.05; Fig. 8C); these changes may explain the
increased transplacental conversion of cortisol to cortisone near
term.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
. Consequently, the secretion of
cortisol into the baboon fetus that predominates during early to
midgestation, presumably due to the relatively high levels of
11ßHSD-1 throughout the syncytiotrophoblast including the
BMm, would decline near term, resulting in
disinhibition of the fetal pituitary-adrenocortical axis, release of
pituitary ACTH (2), and activation/maturation of the fetal
adrenal with de novo cortisol output (3).
|
In previous studies in the baboon we also demonstrated that the late gestational switch in placental glucocorticoid metabolism from reduction to oxidation was regulated by estrogen (1). Thus, we speculate that the developmental change in the ratio of the 11ßHSD enzymes in specific membrane components of the placental syncytiotrophoblast of baboons in the present study is regulated by estrogen. Substantiation of this process would further indicate the integrative role that estrogen has in regulating key aspects of placental differentiation that have a major impact on fetal maturation.
Consistent with our previous studies (8, 9) demonstrating that the expression of 11ßHSD-1 and -2 in baboon syncytiotrophoblast increased with advancing gestation, the total amount of 11ßHSD-2 in whole villous placenta and in specific membrane components of the syncytiotrophoblast (i.e. BMm) determined in this study were higher near term than at midgestation. Similarly, there was a 6-fold increase in the amount of 11ßHSD-1 associated with the MVM, presumably due to an increase in the quantity of MVM between mid- and late gestation, reflected in the current study as a 3-fold increase in the specific activity of the MVM-specific marker alkaline phosphatase.
The EM immunocytochemistry and immunofluorescence results of the current study suggest that 11ßHSD-2, but not 11ßHSD-1, was present in and/or associated with the nuclear envelope of syncytiotrophoblast nuclei. Consistent with these observations, there was abundant 11ßHSD-2 enzyme activity in 25,000 x g fractions of human (17) and baboon (18) term placenta, indicating localization at sites in addition to the endoplasmic reticulum. Using confocal laser microscopy, Shimojo et al. (19) have shown that approximately 40% of total 11ßHSD-2 immunostaining in renal collecting ducts and colonic epithelial cells is nuclear in origin, confirming previous studies (20, 21) demonstrating nuclear renal 11ßHSD activity. However, these researchers as well as others (22) failed to detect 11ßHSD protein in nuclei of human term placenta and thus presumed that 11ßHSD-2 was localized almost exclusively to endoplasmic reticulum (23, 24).
Mechanisms by which proteins uniquely move and insert into specific membranes of polarized cells, including the syncytiotrophoblast (25), are extremely complex and not completely understood (26). Neither 11ßHSD-1 nor 11ßHSD-2 has sorting signals in their ectodomains that would target them to specific membrane fractions. Studies have shown that 11ßHSD-1 is glycosylated (27, 28) and 11ßHSD-2 contains a potential glycosylation site (9) and was indeed detected as a doublet in human and baboon syncytiotrophoblast in the present study as well as our previous study (9). However, despite the fact that glycosylation could affect cellular localization, it has also been shown that modification of such posttranslational processing of other proteins does not necessarily alter sorting (26). Thus, the factors acting to target 11ßHSD-1 to the MVM and 11ßHSD-2 to other syncytiotrophoblast components remain to be elucidated. Recent studies (29) have demonstrated that the ezrin-radixin-moesin family of proteins plays structural and regulatory roles in the assembly and stabilization of specialized plasma membrane domains and that ezrin and related molecules are concentrated in surface projections such as microvilli to link microfilaments to the membrane. Interestingly, ezrin is abundantly expressed in the human placenta and is localized specifically to the microvilli (30). Whether ezrin or other relevant regulatory factors bind and/or complex with the 11ßHSD-1 and/or -2 proteins to provide a mechanism by which the 11ßHSD enzymes are targeted to distinct regions of the syncytiotrophoblast remains to be elucidated.
Recently, it has been shown in the rat placenta that 11ßHSD-1 and -2 were localized primarily to the labyrinth and basal zones, respectively (31). Moreover, the ratio of the mRNAs and activities of 11ßHSD-2 and 11ßHSD-1 changed significantly in late rat gestation (7, 31). Thus, the spatial separation of 11ßHSD-1 and -2 in the syncytiotrophoblast of baboon and human placenta as shown in the present study also appears to occur in the rodent placenta.
In summary, the current study shows that the 11ßHSD-1 and -2 enzymes were localized to different fractions of baboon and human syncytiotrophoblast. 11ßHSD-1 was localized extensively to the MVM, whereas 11ßHSD-2 was located throughout the remainder of the syncytiotrophoblast, including the BMm facing the fetal blood compartment. Moreover, there was a developmental increase in the ratio of 11ßHSD-2 to 11ßHSD-1 in the syncytiotrophoblast membranes juxta the fetal blood compartment, which we propose is consistent with and perhaps the subcellular mechanism responsible for the previously demonstrated switch in transplacental glucocorticoid metabolism from reduction at midgestation to oxidation late in gestation and which appears to be responsible for the activation/maturation of the fetal pituitary-adrenocortical axis.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received January 10, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  G. J. Pepe, M. G. Burch, and E. D. Albrecht Developmental Regulation of the Sodium/Hydrogen Ion Exchangers and Their Regulatory Factors in Baboon Placental Syncytiotrophoblast Endocrinology, June 1, 2006; 147(6): 2986 - 2996. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Myatt Placental adaptive responses and fetal programming J. Physiol., April 1, 2006; 572(1): 25 - 30. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Kadereit, P. Fustier, K. Shojaati, B. M. Frey, F. J. Frey, and M. G. Mohaupt Extracellular ATP Determines 11{beta}-Hydroxysteroid Dehydrogenase Type 2 Activity via Purinergic Receptors J. Am. Soc. Nephrol., December 1, 2005; 16(12): 3507 - 3516. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Johnstone, A. D. Bocking, E. Unlugedik, and J. R.G. Challis The Effects of Chorioamnionitis and Betamethasone on 11{beta}, Hydroxysteroid Dehydrogenase Types 1 and 2 and the Glucocorticoid Receptor in Preterm Human Placenta Reproductive Sciences, May 1, 2005; 12(4): 238 - 245. [Abstract] [PDF]
|
|
|
|
|
|
F. H. Bloomfield, M. H. Oliver, P. Hawkins, A. C. Holloway, M. Campbell, P. D. Gluckman, J. E. Harding, and J. R. G. Challis Periconceptional Undernutrition in Sheep Accelerates Maturation of the Fetal Hypothalamic-Pituitary-Adrenal Axis in Late Gestation Endocrinology, September 1, 2004; 145(9): 4278 - 4285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.M. Driver, S. Rauz, E.A. Walker, M. Hewison, M.D. Kilby, and P.M. Stewart Characterization of human trophoblast as a mineralocorticoid target tissue Mol. Hum. Reprod., December 1, 2003; 9(12): 793 - 798. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. Waddell, S. Hisheh, Z. S. Krozowski, and P. J. Burton Localization of 11{beta}-Hydroxysteroid Dehydrogenase Types 1 and 2 in the Male Reproductive Tract Endocrinology, July 1, 2003; 144(7): 3101 - 3106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Pepe, P. L. Ballard, and E. D. Albrecht Fetal Lung Maturation in Estrogen-Deprived Baboons J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 471 - 477. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. B. Hardy and K. Yang The Expression of 11{beta}-Hydroxysteroid Dehydrogenase Type 2 Is Induced during Trophoblast Differentiation: Effects of Hypoxia J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3696 - 3701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sarkar, S.-W. Tsai, T. T. Nguyen, M. Plevyak, J. F. Padbury, and L. P. Rubin Inhibition of placental 11beta -hydroxysteroid dehydrogenase type 2 by catecholamines via alpha -adrenergic signaling Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2001; 281(6): R1966 - R1974. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Pepe, M. G. Burch, and E. D. Albrecht Estrogen Regulates 11{beta}-Hydroxysteroid Dehydrogenase-1 and -2 Localization in Placental Syncytiotrophoblast in the Second Half of Primate Pregnancy Endocrinology, October 1, 2001; 142(10): 4496 - 4503. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Pepe, M. G. Burch, C. P. Sibley, W. A. Davies, and E. D. Albrecht Expression of the mRNAs and Proteins for the Na+/H+ Exchangers and Their Regulatory Factors in Baboon and Human Placental Syncytiotrophoblast Endocrinology, August 1, 2001; 142(8): 3685 - 3692. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
,
P = 0.06).
