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INSERM, U-422, Unité de Neuroendocrinologie et Physiopathologie Neuronale (V.P., D.C., P.P., J.-C.B.), 59045 Lille Cedex, France; Neuroscience Research Institute, State University of New York (C.M.R., G.L.F., G.B.S.), Old Westbury, New York 11568; and the Division of Psychiatry, Harvard Medical School, Brigham and Women’s Hospital (G.L.F., G.B.S.), Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Dr. Vincent Prevot, INSERM, U-422, Unité de Neuroendocrinologie et Physiopathologie Neuronale, place de Verdun, 59045 Lille Cedex, France. E-mail: prevot{at}biserte.lille.inserm.fr
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-estradiol or
testosterone had no effect. 17ß-Estradiol conjugated to BSA
(E2-BSA) also stimulated NO release, suggesting mediation
by a membrane surface receptor. Tamoxifen, an estrogen receptor
inhibitor, antagonized the action of both 17ß-estradiol and
E2-BSA. Furthermore, estradiol-stimulated NO stimulates
GnRH release. This was demonstrated by hemoglobin (a NO scavenger),
N
-nitro-L-arginine methyl
ester, and
L-N5-(1-iminoethyl)ornithine
(nitric oxide synthase inhibitors) inhibition of estradiol stimulated
NO and GnRH release. In this regard,
L-N5-(1-iminoethyl)ornithine,
specific for endotheliol constitutive nitric oxide synthase, was
significantly more potent, suggesting that the estradiol-stimulated NO
release arose from vascular endothelial cells. Additionally, the
NO-stimulated GnRH release occurs via guanylyl cyclase activation in
GnRH nerve terminals, as ODQ, a potent and selective inhibitor of
NO-sensitive guanylyl cyclase, abolished the estradiol-stimulated GnRH
release. The results suggest that at physiological concentrations,
17ß-estradiol may have immediate actions on ME endothelial cells via
nongenomic signaling pathways leading to NO-stimulated GnRH
release. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this regard, the present study demonstrates that rat ME responds to acute estradiol exposure by releasing NO. We further demonstrate that a consequence of this estrogen-stimulated NO release is the release of GnRH from ME fragments. Taken together, this study represents the first study in which estrogen is demonstrated to exert acute actions that have immediate biological consequences, i.e. hormonal release. Furthermore, of equal importance is the demonstration that this signaling process can be initiated and regulated by vascular endothelial cells, demonstrating the presence of neurovascular regulatory processes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Dissection procedure
Animals were killed by decapitation. After rapid removal of the
brain, the median eminence and associated vascular tissues were
dissected under a binocular magnifying glass by cutting with Wecker’s
scissors (Moria, France) the floor of the brain within the following
limits: posterior border of the optic chiasm and the anterior border of
the mamillary bodies. With this type of dissection, pieces containing
ME were obtained with very little arcuate nucleus fragments. The total
dissection time was less than 3 min from decapitation.
Incubation system
After dissection, ME fragments were washed twice in Krebs-Ringer
bicarbonate/glucose buffer (pH 7.4) containing bacitracin (23
µM; Sigma Chemical Co., St. Louis, MO) in an
atmosphere of 95% O2–5% CO2 and then
immersed in Eppendorf tubes containing 700 µl of the same buffer.
Three ME fragments were incubated in each tube.
NO determination
The tissue fragments were incubated as described above. NO
release was measured directly using a NO-specific amperometric probe
(World Precision Instruments, Sarasota, FL) as described previously (9, 22, 23, 24). The tip diameter of the probe (25 µm) permitted the use of a
micromanipulator (Zeiss-Eppendorf, Hamburg,
Germany) to position the sensor 5 mm above the tissue surface.
Calibration of the electrochemical sensor was performed by use of
different concentrations of a nitrosothiol donor
S-nitroso-N-acetyl-D,L-penicillamine,
as described in detail previously (25). The probe needed 15 min to
stabilize after its immersion in the Krebs-Ringer bicarbonate/glucose
buffer medium, and baseline levels of NO release were determined by
evaluation of the NO concentration released from unstimulated ME
fragments. Drugs were added to the buffer after the stabilization time,
and NO release was monitored for 20 min. ME fragments were stimulated
with various concentrations of 17ß-estradiol
(10-13–10-7 M) or
17ß-estradiol conjugated to BSA (E2-BSA;
10-13–10-7 M 17ß-estradiol) or
testosterone (10-13–10-7 M; four
tubes were run for each condition). ME fragments were stimulated with
17-estradiol (10-8 M; n = 4);
tamoxifen (10-8 M), an estrogen receptor
antagonist (n = 4); tamoxifen (10-8 M)
plus 17ß-estradiol (10-8 M; n = 4); or
tamoxifen (10-8 M) plus E2-BSA
(10-8 M; n = 4). Tamoxifen was added to
the milieu 5 min before 17ß-estradiol or E2-BSA. The
concentration of NO gas in solution was measured in real-time with
computer data acquisition (DUO 18, World Precision Instruments) at a
sampling rate of 6/s (22, 23). NO release was evaluated with
simultaneous measurement of untreated control ME fragments with a
second probe to allow comparison of each treatment group to its own
control preparation. Data acquisition was performed by the
computer-interfaced DUO-18 software (World Precision Instruments). The
experimental values were then transferred to Sigma-Plot and Sigma-Stat
(Jandel, San Rafael, CA) for graphic representation and evaluation.
GnRH secretion determination
The tissue fragments were incubated as described for the NO
determination. Drugs were added to the medium after an equilibration
period of 15 min. The stimulation period was 10 min. NOS inhibitors,
N-nitro-L-arginine methyl ester
(L-NAME; 4 x 10-6 M) or
L-N5-(1-iminoeth-yl)ornithine
(L-NIO; 4 x 10-5, 4 x 10-6,
5 x 10-7, and 5 x 10-8
M), or the potent and selective inhibitor of NO-sensitive
guanylyl cyclase,
1H-[1,2,4]oxadiazolo[4,3]quinoxalin-1-one (ODQ; 2 x
10-6 M) (26, 27, 28, 29), were added to the milieu 5
min before 17ß-estradiol or E2-BSA. L-NIO is a well known
inhibitor of NOS (30) and shows a better inhibition of endotheliol
constitutive NOS (IC50 = 0.5 x
10-6 M) (30) than neuronal NOS (nNOS;
IC50 = 3.9 x 10-6 M) (31).
Four tubes were run for each experiment. At the end of each experiment,
the ME fragments were immediately removed, and EDTA was added to the
milieu (final concentration, 10-2 M). GnRH
concentrations were measured in duplicate by RIA as described
previously (9). The sensitivity for GnRH was 1.2 pg/tube, and the
intraassay variability was 3.4%. GnRH antibody was a gift from Dr.
Tramu of the CNRS URA 339, Université Bordeaux I (Talence,
France). All drugs were purchased from Sigma Chemical Co.
(St. Quentin Fallavier, France), except L-NIO and ODQ, which
were purchased from Calbiochem (France Biochem, Meudon,
France).
Plasma estradiol and testosterone determinations
After decapitation, trunk blood was collected into vials
containing 50 µl 0.3 M EDTA and centrifuged. Plasma was
stored at -20 C until estradiol and testosterone RIAs.
Plasma estradiol was measured using a RIA kit optimized for the direct quantitative determination of very low concentrations of 17ß-estradiol in human serum and plasma (e.g. in children), purchased from Sorin Biomedica (Antony, France). The assay sensitivity was 0.2 pg/tube, and intra- and interassay variances were 5.6% and 7.3%, respectively.
Testosterone levels were measured using a RIA kit optimized for the direct quantitative determination of very low concentrations of testosterone in human serum and plasma, purchased from Amersham (Les Ulis, France). The assay sensitivity was 5 pg/tube, and intra- and interassay variances were 5.1% and 11.5%, respectively.
Statistics
All experiments were repeated a minimum of four times,
i.e. at least four tubes where run for each condition. The
results were analyzed by one-way ANOVA with repeated measures, and the
significance of differences was determined by the Student-Newman-Keuls
test. The differences between the means of two groups were calculated
by Student’s t test, where P < 0.05 was
considered significantly different.
Morphology
To assure that tissues were able to maintain a high level of
biological organization during the experiments, which may reflect their
responses to stimulation, some ME fragments were immersed for 2 h
in a fixative mixture of 2% paraformaldehyde, 0.2% picric acid, and
0.1% glutaraldehyde in 0.1 M phosphate buffer, pH 7.4, for
2 h at 4 C after a 15-min stabilization time plus a 20-min
stimulation time. Pieces of tissue were postfixed for 1 h at room
temperature with 1% OsO4 in phosphate buffer and were
embedded in Araldite after dehydration.
Semithin sections (1–2 µm thick) were obtained to observe the tissue conservation at the light microscopy level and ultrathin sections (80–90 nm thick) were obtained to observe the ultrastructural aspect of the ME.
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Results |
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17ß-Estradiol stimulates NO release
17ß-Estradiol induced a concentration-dependent increase in NO
release from ME fragments (Figs. 1
and 2). Increasing concentrations of
17ß-estradiol (10-11–10-7 M)
resulted in a dose-dependent increase in NO release, with a maximal
effect observed after 10-8 M 17ß-estradiol
treatment (Fig. 1). NO release peaked after 2 min of 17ß-estradiol
treatment of the ME fragments (Fig. 2). Addition of 10-12
M 17ß-estradiol failed to induce a significant increase
in NO release. The median effective concentration (EC50)
value for 17ß-estra-diol-induced NO release was approximately
10-10 M.
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).
The action of estradiol is steroid specific
17-Estradiol (10-8 M) did not
stimulate NO release (Fig. 2). Tamoxifen (10-8
M), an estradiol receptor inhibitor, significantly
diminished (Fig. 2; P < 0.01)
17ß-estradiol-stimulated NO release.
17ß-Estradiol acts at a surface receptor
17ß-Estradiol appears to stimulate NO release by acting at the
membrane surface, not on an intracellular receptor. E2-BSA
(10-8 M), which does not penetrate the
cellular membrane due to its size, also stimulates NO release from ME
fragments within 2 min of its application in a tamoxifen-sensitive
manner (Fig. 2). As for 17ß-estradiol, E2-BSA-stimulated
NO release is dose dependent (Fig. 1). Stimulation of the ME with
10-11 M E2-BSA failed to stimulate
a significant increase in NO release. The median effective
concentration (EC50) for E2-BSA-stimulated NO
release is approximately 3 x 10-10
M.
17ß-Estradiol and 17ß-estradiol coupled to BSA stimulate a
rapid GnRH secretion from ME nerve terminals
17ß-Estradiol (10-10 and 10-8
M), like E2-BSA (10-8
M), induced a release of GnRH from ME fragments (Figs. 3 and 4) within 10 min of their
application. GnRH levels were significantly increased in the medium
after 17ß-estradiol or E2-BSA addition (Fig. 4; P < 0.05) compared
with those in the untreated groups. E2-BSA was as potent as
17ß-estradiol in inducing GnRH release from ME fragments, whereas
17-estradiol had no effect on GnRH release (Fig. 4).
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). The same results were obtained for
17ß-estradiol.
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). The same results were obtained for
17ß-estradiol.
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).
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Tissue preservation
Structural examination of the ME fragments with light (Fig. 8A) and electronic (Fig. 8B) microscopies
demonstrated that the tissues were in an excellent state of
preservation after a 35-min incubation period. The parenchyme of the ME
external zone was well preserved (Fig. 8), the nerve endings were in
close contact with ependymal processes that reached the portal
capillary bed. Inside the nerve endings and tanycytic end feet,
the different organelles were also well preserved. The parenchymatous
and endothelial basement membranes were well visible (Fig. 8b).
Together, these observations proved that even after a 35-min incubation
period, the ME structure was comparable to that observed upon placing
the tissues immediately, without delay, in the fixative solution (33),
and was compatible with the occurrence of physiological processes
throughout the experiment.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-estradiol and
testosterone action. The fact that E2-BSA, an impermeable
cell membrane estradiol analog, also stimulates NO release indicates
that this receptor is located on the surface of the NOS-containing
cells. Furthermore, 17ß-estradiol- and E2-BSA-stimulated
GnRH release is inhibited by hemoglobin (a NO scavenger), and by L-NAME
and L-NIO, NOS inhibitors, indicating that the effects of estradiol on
GnRH secretion are mediated by coupling to NO. Moreover, according to
Rees et al. (30) and Moore et al. (31), L-NIO is
much more potent in inhibiting ecNOS than nNOS at the concentrations
used in this study, suggesting that the major source of NO after
E2-BSA or 17ß-estradiol stimulation is endothelial in
origin. Furthermore, the NO stimulation of GnRH release occurs via the
soluble guanylyl cyclase activation in the GnRH nerve terminals, as
estradiol-stimulated GnRH release was inhibited by ODQ, a NO-sensitive
guanylyl cyclase inhibitor (26, 27, 28, 29). Taken together, the rapid action
of estradiol on GnRH release from ME fragments appears to be mediated
by a NOS-coupled estrogen receptor located on the surface of
endothelial cells found in the ME fragments. NO release has been shown to be crucial for the occurrence of basal LH release in males (12) and the LH surge in ovariectomized females treated with estradiol plus progesterone (34, 35). Further, NO donors have been shown to be able to induce LH surge in estradiol-treated ovariectomized females (36) and thus to have a progesterone-like effect. Very recent findings show that estradiol stimulates nNOS expression in the preoptic area and in that way exerts a facilitatory influence on NO-producing neurons (29). The NO released appears to be able to modulate the activity of GnRH neurons (29). These observations implicate neuronal NO in the regulation of GnRH cell activity in the preoptic area. Contrary to these results, the present study, in accordance with our previous work (9), suggests that at the ME level, the NO implicated in the modulation of GnRH release is endothelial in origin rather than neuronal. This is consistent with the fact that unlike in the preoptic area where GnRH perikarya are surrounded by nNOS-containing cells, nNOS fibers and GnRH fibers in the ME are distributed separately in the internal and external zones, respectively (37). Further, in the ME, ecNOS immunoreactivity is observed in endothelial cells of the pituitary portal blood vessels (38), located at the immediate proximity of the GnRH terminals (33). The endothelial origin of NO secreted from ME fragments is strengthened by the results of a previous study which showed that central administration of ecNOS antisense is more efficacious than nNOS antisense administration in suppressing the estradiol-/progesterone-induced LH surge in ovariectomized females (10).
Regarding estradiol, it has been implicated in vascular reactivity (for review, see Refs. 39, 40) and more particularly in the stimulation of NO synthesis (40, 41). The long term stimulatory effects of estradiol on NO activity may also take place by increasing ecNOS synthase production (14, 42, 43). Estradiol can increase ecNOS expression within 8 h after its application on human vein endothelial cells via a cytosolic receptor-mediated system, and this action can be inhibited by the estrogen receptor antagonist, tamoxifen (15). The presence of two left-half palindromic sites of an estrogen receptor-binding element on the human ecNOS gene supports a potential receptor-mediated effect of estrogen on gene expression (44). Our study clearly shows that beside its long term action via a nuclear receptor on NO release from endothelia (15, 44), estradiol can have a short term stimulating action, i.e. NO release, via a specific membrane estrogen receptor on ME fragments. Tamoxifen is considered to be an antagonist at the nuclear estrogen receptor, but our results, in accordance with those of others (45, 46), suggest that tamoxifen antagonizes the effect of estradiol on its membrane receptor. In this way, tamoxifen has been shown to block the internalization of the nonactivated membrane estrogen receptor in the goat uterus (47).
This acute effect of estrogen on GnRH release from mediobasal hypothalamus has been poorly investigated compared with processes involving progesterone (48). Only one study showed that 17ß-estradiol had a receptor-mediated effect on GnRH release within 30 min in response to depolarization evoked by elevating K+ concentration (46). These researchers concluded that a membrane effect of 17ß-estradiol is present (46). In the present study we substantiate this observation and provide a mechanism, i.e. via NO, for the acute stimulatory effect of 17ß-estradiol on GnRH release. We surmise that estradiol-stimulated NO causes activation of the soluble guanylyl cyclase in GnRH terminals and results in cGMP production and, thus, in a depolarization involving a cationic conductance (49) that leads to GnRH release (46). Our findings are in accordance with recent evidence showing that NO stimulates GnRH release by an intracellular signal transduction process involving cGMP (34, 50, 51). As suggested by others, NO may also activate cyclooxygenase in GnRH terminals and/or glia that results in the production of PGE2 (52). PGE2 would then lead to the mobilization of calcium from intracellular stores (53) and cAMP formation (54), which finally induces the exocytosis of GnRH secretory granules (52). In this regard, a recent study showed PGE2 receptor gene expression in GnRH neurons (55).
In the male rat, estrogen plasma levels, as shown by our results, are comparable to those found in early proestrus female rats (33). Part of this plasma estradiol appear to arise from testosterone aromatization (32). In the present study we show that testosterone, in contrast to estradiol, is unable to stimulate NO release from male rat ME fragments. Our results suggest that on ME fragments, testosterone does not act on membrane receptors coupled to NOS activity and is not metabolized into estradiol. The latest observation is consistent with the fact that aromatase is not expressed in the ME (56). In male rats the effect of estrogen on GnRH release has not been investigated. One study on the adult male quail showed that basal GnRH release was increased by short term exposure of hypothalamic slices to 17ß-estradiol, whereas testosterone had no effect (57). In female rats estrogen has both stimulatory and inhibitory effects on GnRH release depending on their plasma levels (for review, see Refs. 58, 59). Kalra and Kalra (60) and Smith et al. (61) have shown that on diestrous day 1 and proestrus, GnRH output increases markedly, coincident with the rise in serum 17ß-estradiol. Moreover, we have shown in a previous work (33) that the peak level of estradiol obtained at 0900 h on proestrus was associated with GnRH release between 0900–1000 h on proestrus. In this same study (33) a new peak of estradiol appeared at 1700 h on proestrus, which might be associated with the GnRH surge that might occur at the same time, as shown by Sarkar and Minami (62).
The local and acute effect of estradiol on ME endothelium might have physiological implications, the major being the modulation of pulsatile GnRH secretion (63, 64) leading to LH release. It could also be implied in circumstances where a role for estrogen has been demonstrated, such as in mood disturbance (65, 66), mental stress (67), and premenstrual syndrome (65). In addition, extrapolation from the present neuroendocrinological model appears to identify the existence of another important mode of communication between the brain and the blood. Indeed, as shown by the present study and supported by our previous work (9), various signaling molecules, such as estradiol, morphine, and anandamide, conveyed in the blood can communicate with the brain without penetrating it, via NO production originating from the endothelium. We surmise that in other brain areas, molecules that cannot penetrate the blood-brain barrier could also modulate neuronal activity via endothelial NO signaling.
In summary, these observations are in direct line with our previous study demonstrating that rat ME produces NO in response to stimulatory molecules acting on ME endothelial cells (9). In the present study, 17ß-estradiol coupling to endothelial NO stimulates GnRH release from ME fragments via a membrane receptor. These effects occur at physiological concentrations and may play an important role in the modulation of pulsatile GnRH secretion from GnRH neuroendocrine terminals of the ME and thus represent a synchronizing link to anatomically scattered GnRH neurons (63, 64, 68). Additionally, this work demonstrates that the vascular endothelium in the ME is involved in the modulation of neurosecretions.
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Acknowledgments |
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Footnotes |
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Received May 5, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in the release of luteinizing hormone-releasing hormone from the
developing female hypothalamus. Proc Natl Acad Sci USA 87:9698–9702 with the secretion of neuroactive substances that stimulate
the release of luteinizing hormone-releasing hormone. Endocrinology 138:19–25 (ER) and estrogen receptor-ß (ERß) messenger
ribonucleic acid in the wild-type and ER-knockout mouse.
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 R. Clarke, F. Leonessa, J. N. Welch, and T. C. Skaar Cellular and Molecular Pharmacology of Antiestrogen Action and Resistance Pharmacol. Rev., March 1, 2001; 53(1): 25 - 72. [Abstract] [Full Text] [PDF]
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J. Kamegai, H. Tamura, T. Shimizu, S. Ishii, H. Sugihara, and I. Wakabayashi Estrogen Receptor (ER){{alpha}}, But Not ER{beta}, Gene Is Expressed in Growth Hormone-Releasing Hormone Neurons of the Male Rat Hypothalamus Endocrinology, February 1, 2001; 142(2): 538 - 543. [Abstract] [Full Text] [PDF]
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 L. Tseng, J. Mazella, M. S. Goligorsky, C. M. Rialas, and G. B. Stefano Dopamine and Morphine Stimulate Nitric Oxide Release in Human Endometrial Glandular Epithelial Cells Reproductive Sciences, November 1, 2000; 7(6): 343 - 347. [Abstract] [PDF]
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K. J. Suter, J.-P. Wuarin, B. N. Smith, F. E. Dudek, and S. M. Moenter Whole-Cell Recordings from Preoptic/Hypothalamic Slices Reveal Burst Firing in Gonadotropin-Releasing Hormone Neurons Identified with Green Fluorescent Protein in Transgenic Mice Endocrinology, October 1, 2000; 141(10): 3731 - 3736. [Abstract] [Full Text] [PDF]
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 G. B. Stefano, P. Cadet, C. Breton, Y. Goumon, V. Prevot, J. P. Dessaint, J.-C. Beauvillain, A. S. Roumier, I. Welters, and M. Salzet Estradiol-stimulated nitric oxide release in human granulocytes is dependent on intracellular calcium transients: evidence of a cell surface estrogen receptor Blood, June 15, 2000; 95(12): 3951 - 3958. [Abstract] [Full Text] [PDF]
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A. B Ropero, E. Fuentes, J. M Rovira, C. Ripoll, B. Soria, and A. Nadal Non-genomic actions of 17{beta}-oestradiol in mouse pancreatic {beta}-cells are mediated by a cGMP-dependent protein kinase J. Physiol., December 1, 1999; 521(2): 397 - 407. [Abstract] [Full Text] [PDF]
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 G. B. Stefano, V. Prevot, J.-C. Beauvillain, C. Fimiani, I. Welters, P. Cadet, C. Breton, J. Pestel, M. Salzet, and T. V. Bilfinger Estradiol Coupling to Human Monocyte Nitric Oxide Release Is Dependent on Intracellular Calcium Transients: Evidence for an Estrogen Surface Receptor J. Immunol., October 1, 1999; 163(7): 3758 - 3763. [Abstract] [Full Text] [PDF]
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H C Christian and J F Morris Rapid actions of 17{beta}-oestradiol on a subset of lactotrophs in the rat pituitary J. Physiol., March 1, 2002; 539(2): 557 - 566. [Abstract] [Full Text] [PDF]
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