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Endocrinology Vol. 148, No. 3 1440-1444
Copyright © 2007 by The Endocrine Society

Ontogeny and Effects of Hypothalamic Pituitary Disconnection on Formation of Inositol Trisphosphate in Fetal Sheep Pituitary Cells

Luke C. Carey, Stephen B. Tatter and James C. Rose

Departments of Obstetrics/Gynecology (L.C.C., J.C.R.), Neurosurgery (S.B.T.), and Physiology/Pharmacology (J.C.R.), and The Center for Research in Obstetrics and Gynecology (L.C.C., J.C.R.), Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1066

Address all correspondence and requests for reprints to: Luke C. Carey, Ph.D., Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1066. E-mail: lcarey{at}wfubmc.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In late gestation fetal sheep, the pituitary becomes increasingly responsive to stimulation by arginine vasopressin (AVP). This change appears to be one important factor mediating the plasma cortisol surge, a critical developmental event. It is not known precisely why pituitary corticotropes become more responsive at this time. In this study we examined the possibility that changes in second messenger generation [inositol trisphosphate (IP3)] are responsible. Two studies were undertaken. The first was an ontogeny study, where pituitaries were isolated from 100-, 120-, and 140-d gestational age (dGA) fetal sheep. Cells were cultured, stimulated with AVP, and the formation of IP3 assessed. The amount of IP3 generated increased with gestational age (percent increases from unstimulated controls were 4.6, 11.5, and 21.5 for 100, 120, and 140 dGA, respectively), with significant differences between the 140-dGA group and both earlier groups apparent. The second study examined the impact of 120-dGA hypothalamo-pituitary disconnection (HPD), which prevents corticotrope maturation, on responsiveness of pituitary cells isolated from 140-dGA fetuses. Cells were stimulated with AVP, and the formation of IP3 and secretion of ACTH were assessed. Significantly less IP3 was formed, and ACTH secreted in cells from HPD compared with control fetuses (IP3 and ACTH levels were 50% and 35% lower, respectively). Results from the HPD study demonstrate that the ontogenic changes in IP3 after AVP require an intact hypothalamic-pituitary-adrenal axis. These findings suggest that heightened second messenger generation may be a key reason for increased ACTH secretory responsiveness to AVP in the late gestation sheep fetus.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IN THE NEAR term fetus, plasma cortisol concentrations increase dramatically. For example, in fetal sheep, where term is around 147 d, concentrations are negligible at 120 d gestational age (dGA) but close to 90 ng/ml after 140 dGA (1). This late gestation surge in fetal plasma cortisol concentrations is a crucial developmental phenomenon, stimulating lung and other organ development. A number of changes in the hypothalamic-pituitary-adrenal (HPA) axis appear to underlie the surge, including elevated plasma concentrations of bioactive ACTH (2, 3) and increased adrenal responsiveness (4, 5, 6, 7). One other important change evident is increased pituitary responsiveness to arginine vasopressin (AVP). With advancing gestational age, it has been demonstrated in fetal sheep that corticotrope maturation is both morphological as well as functional. For instance, at around 100 dGA, corticotropes have what is termed a "fetal" appearance and are most responsive to stimulation by corticotropin releasing factor (CRF), while corticotropes from older fetuses (i.e. 140 dGA) resemble adult corticotropes in appearance and are more responsive to AVP (8, 9, 10, 11).

Exactly why late gestation fetal corticotropes become more responsive to AVP is unclear, although several possible explanations exist. We recently examined changes in AVP receptor expression with the notion that perhaps this change is simply a reflection of increased expression (12). However, contrary to our initial hypothesis, we found that mRNA and protein expression of the pituitary specific vasopressin receptor (V1b) involved in ACTH secretion in fact decreased with gestational age. Furthermore, hypothalamo-pituitary disconnection (HPD), which prevents the cortisol surge and morphological maturation of corticotropes from occurring, did not alter the pattern of V1b expression.

Another possible explanation is that changes in AVP signal transduction underlie the increased responsiveness. A sequence of events mediate AVP-induced ACTH release, beginning with the hormone binding to its G protein-coupled V1b receptor (13, 14). This binding induces a conformational change in receptor structure, leading to G protein dissociation and activation of membrane-associated phospholipase C (PLC) (13, 14). Subsequent cleavage of phosphatidylinositol-bisphosphate (4, 5) by PLC results in the formation of second messengers inositol trisphosphate (IP3) (1, 4, 5) and diacylglycerol (15). Water-soluble IP3 then diffuses into the cytosol, where it binds to specific receptors on the endoplasmic reticulum and triggers rapid release of calcium ions from IP3 gated channels (16). The calcium ions in turn stimulate exocytosis of ACTH containing storage granules, and IP3 is subsequently metabolized through a series of steps to IP2, IP, free inositol, and ultimately phosphatidylinositol-bisphosphate (17).

AVP-stimulated ACTH release is less sensitive to feedback inhibition by glucocorticoids than is CRF (18, 19, 20). Studies conducted by Rabadan-Diehl and Aguilera (21) suggest that this is a consequence of increased coupling of the V1b receptor to PLC. They found that pituitaries from rats treated with dexamethasone for 7 d exhibited heightened formation of inositol phosphates (IP, IP2, and IP3) after stimulation with AVP. These effects were noted despite decreased overall AVP binding.

These findings led us to hypothesize that as gestation proceeds in the fetal sheep and plasma cortisol concentration increase, the amount of second message generated after AVP binding to its receptor on corticotropes increases, thus enhancing the ACTH secretory responses to AVP close to term. Several experiments were undertaken to test this hypothesis. First, we performed an ontogenic assessment of changes in the generation of inositol phosphates in pituitary cells, and then examined the effects of HPD on both IP formation and secretion of ACTH after AVP stimulation, with the expectation that HPD would prevent corticotrope maturation and, therefore, the increased responsiveness to AVP from occurring.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Time-dated, mixed-breed, pregnant sheep were obtained from local suppliers and housed in straw-lined pens with ad libitum access to food and water. Animals were acclimated for 4–5 d before killing or surgery. The Wake Forest University Animal Care and Use Committee approved all procedures.

Ontogeny study
Sheep carrying fetuses of approximately 100 (n = 7), 120 (n = 6), and 140 dGA (n = 11) were used. After killing by sodium pentobarbital overdose, fetal anterior pituitaries were immediately dissected and placed in ice-cold HEPES dissociation buffer. Pituitaries were then cut into small pieces using sterile scalpel blades, washed several times with HEPES dissociation buffer, and then placed in 5 ml 0.04% collagenase II (Worthington Biochemical Corp., Lakewood, NJ). Cells were dissociated by gentle rocking at 37 C for approximately 2 h. DNase (150 U; Sigma, St. Louis, MO) was added after 1 h. When dissociation was complete, 5 ml DMEM/F12 medium containing 10% fetal calf serum (complete medium) was added, and the solution was then centrifuged for 5 min 400 x g. Cells were subsequently washed with complete medium and centrifuged a further two times, before being plated at a density of 0.6 x 105 cells per well (500 µl) in 48 well culture plates. Half of the cells isolated from a single pituitary were designated for AVP treatment, while half were used as controls. After 24 h, 0.5 µl [3H]-myo-inositol (PerkinElmer, Boston, MA) was added to each well. At 46 h, complete medium was removed and replaced with DMEM/F12 containing 0.1% polypep (Sigma) and 10 mM LiCl (incomplete medium). LiCl inhibits the recycling of inositol phosphate to inositol. At 48 h, cells were stimulated for 30 min with incomplete medium containing 100 nM AVP (Sigma). This concentration of AVP induces a maximum secretory response in sheep pituitary cells in vitro (22). The duration of stimulation was chosen on the basis of preliminary findings and is in keeping with that used in other studies (21, 23). Wells containing control cells received incomplete medium alone. Medium was then removed and the stimulation halted by adding 0.5 ml ice-cold stop solution (1 M KOH, 18 mM Na borate, 3.8 mM EDTA, 7.6 mM NaOH), and neutralized with 0.5 ml 7.5% HCl. The resultant 1-ml solution, containing lysed cells, was frozen at –80 C for later analysis of IP content by anion exchange chromatography.

HPD study
HPD of fetal sheep (n = 9) was performed on, or close to, 120 dGA using a slightly modified (12) previously described technique (24). Control fetuses were sham operated (n = 7), where the pituitary stalk was exposed, but not severed. Maternal venous catheters were inserted, and antibiotics (gentamicin; Abbott Laboratories, North Chicago, IL; and ampicillin; American Pharmaceutical Partners, Inc., Schaumburg, IL) and an antiinflammatory (ketoprofen; Fort Dodge Animal Health, Overland Park, KS) were administered for 2 d after surgery. At around 140 dGA, fetal arterial blood samples were obtained for plasma cortisol measurement, and pituitaries were removed as already described. Completeness of HPD was visually assessed at this time. After dispersion, cells were plated at densities of 0.6 x 105 and 2.0 x 105 cells/well to examine the formation IPs (as in the ontogeny study) and ACTH secretion, respectively. For the ACTH secretion study, cells were cultured for 46 h in complete medium and then incubated for 2 h with DMEM/F12 containing 0.1% polypep (incomplete; Sigma). Subsequently, cells were treated for 2 h with incomplete medium alone, incomplete medium + 100 nM AVP, or incomplete medium + 10 nM CRF. The concentration of CRF used induces maximum secretion in sheep pituitary cells in vitro (22). Medium was then immediately frozen at –80 C for later ACTH analysis.

Anion exchange chromatography
Polyprep columns (Bio-Rad, Hercules, CA) were loaded with a 1.5-ml slurry containing formate form AG1-X8 resin (Bio-Rad) and distilled water in a 1:1 ratio. After the resin had packed, samples were added and allowed to drip through. Adding 8 ml distilled water and 8 ml buffer no. 2 (5 mM Na borate, 60 mM Na formate) then eluted free inositol and glycerophosphoinositides, respectively. IP metabolites were then eluted in stepwise fashion by the addition of buffers containing increasing concentrations of NH4 formate. Three milliliters of each eluent were collected for ß counting in glass vials containing 15 ml liquid scintillation fluid, and columns were rinsed with an additional 7 ml of the eluting buffer before the succeeding elution: buffer No. 3 (100 mM formic acid, 400 mM NH4 formate) eluted inositol mono and bisphosphates; and buffer No. 4 (100 mM formic acid, 1 M NH4 formate) eluted IP3s.

It should be noted that although IP3 is the second messenger per se, total inositol phosphates were measured to account for degradation of IP3 to IP2 and IP. As already noted, LiCl prevents further recycling of IP to inositol. In all analysis, IP3 and total IPs (IP, IP2, and IP3) were assessed. This method (generously provided by Dr. Greti Aguilera) was adapted from that developed by Berridge et al. (25).

ACTH and cortisol measurement
Cell medium ACTH and fetal plasma cortisol concentrations were measured using commercial RIA kits (DSL, Webster, TX), where minimum detection limits were 3.5 pg/ml (ACTH) and 0.6 ng/ml (cortisol). Coefficients of variation were 6.0% intraassay and 7.0% interassay for ACTH, and 4.2% intraassay and 7.0% interassay for cortisol.

Statistical analysis
Data pertaining to the IP ontogeny study were non-normally distributed and, therefore, compared using the Kruskal-Wallis one-way ANOVA on ranks, and Dunn’s post hoc test. Sham and HPD IP3 and total IP data were also non-normally distributed and compared by Mann-Whitney rank sum test. ACTH secretion was compared by two-way ANOVA and Newman-Keuls multiple comparison procedure. Data are presented as mean ± SEM, and differences were considered to be significant when P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Ontogeny study
The IP ontogeny results are presented in Fig. 1Go. The pattern was similar for both IP3 and total IPs, with increases in formation after AVP simulation and advancing gestational age apparent. The amount of IP3 and total IPs generated in cells isolated from 140-dGA fetuses was significantly greater than that formed in 100-dGA cells (P < 0.05 for both). Cell viability was always greater than 90%.


Figure 1
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  		FIG. 1. Ontogeny of IP3 and total IP formation in ovine pituitary cells after stimulation with AVP. Cells were isolated from 100-, 120-, and 140-dGA fetuses. Control cells were unstimulated. Groups with different letters are significantly different (P < 0.05; n = 6–11 fetuses per group).

 
HPD study
Plasma cortisol concentrations as determined just before killing were significantly lower in HPD (4.8 ± 0.6 ng/ml) compared with sham-operated fetuses (18.6 ± 3.8 ng/ml) (P = 0.001).

After stimulation with AVP, the formation of both IP3 and total IPs was significantly lower in cells from HPD fetuses (P = 0.002; Fig. 2Go).


Figure 2
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  		FIG. 2. IP3 and total IP levels in pituitary cells stimulated with 100 nM AVP. Cells were isolated from 140-dGA sham or HPD fetuses. Control cells were unstimulated. An asterisk indicates a significant difference between the sham and HPD group (P < 0.05; n = 7–9 fetuses per group).

 
Pituitary cells isolated from HPD fetuses secreted significantly less ACTH than those from sham counterparts after AVP stimulation (P < 0.001; Fig. 3Go). HPD did not alter CRF-induced ACTH secretion (Fig. 3Go). For reference, baseline (control) ACTH levels were 194 ± 12 and 176 ± 15 pg/2.0 x 105 cells in the sham and HPD groups, respectively. There was no difference in viability between cells isolated from sham and HPD fetuses (both were greater than 90% as determined by trypan blue exclusion), and the total number of cells obtained per pituitary was similar between the two groups (1.5 ± 0.1 x 106 vs. 1.4 ± 0.1 x 106 cells for sham and HPD, respectively).


Figure 3
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  		FIG. 3. ACTH secretion from pituitary cells stimulated with 100 nM AVP or 10 nM CRF. Cells were isolated from 140-dGA sham or HPD fetuses. Control cells were unstimulated. An asterisk indicates a significant difference between the sham and HPD group (P < 0.05; n = 7–9 fetuses per group).

 
Regression analysis of IP3 and total IP formation and ACTH secretion is presented in Fig. 4Go. For this, IP and ACTH results obtained from individual pituitaries were averaged and paired. There was a significant positive correlation between the two variables for both IP3 (P = 0.03; R = 0.67) and total IPs (P = 0.03; R = 0.69).


Figure 4
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  		FIG. 4. Regression analysis of ACTH secretion and IP3 (A) and total IP formation (B) in cells isolated from 140-dGA sham and HPD fetuses. Open squares represent values from sham cells, and closed squares represent values from HPD cells.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study we found that the formation of inositol phosphates, including IP3, after stimulation with AVP increased with advancing gestational age in pituitary cells isolated from fetal sheep. Furthermore, we noted that disconnecting the hypothalamus from the pituitary (HPD) prevented these changes from occurring.

It is well accepted that plasma cortisol and bioactive ACTH concentrations increase with advancing gestation in the fetal sheep (1). The cortisol "surge" is a crucial developmental event and one that is not completely understood. One of the changes at the level of the pituitary, which appears to be important in mediating this surge, is altered corticotrope responsiveness to AVP (10, 11). Along with the already noted changes in bioactive ACTH and cortisol, the pituitary becomes increasingly responsive to AVP as gestation proceeds. This development would appear to be a crucial adaptation for maintaining ACTH secretion because pituitary responsiveness to CRF decreases over this time. Although it has been recognized for some time that the pituitary becomes more responsive to AVP in the late gestation fetal sheep, the precise reason for this has been unclear. The novel findings in this study suggest that the primary reason for the heightened ACTH response to AVP is increased formation of the second messenger IP3.

We found that the formation of both IP3 and total IPs in pituitary cells isolated from fetal sheep increased in an ontogenic manner after stimulation with AVP. The sampling regimen used spans the period of relatively low (120 dGA) to high (140 dGA) HPA axis activity, while the pattern of change observed is similar to that of plasma ACTH and cortisol concentrations. The fact that the change in second message expression also correlated with altered ACTH responsiveness to AVP implies that this development is essential for maintaining ACTH and, therefore, cortisol output.

It is possible that other changes at the level of the pituitary, particularly those related to receptor expression and binding, contribute to the noted increased responsiveness. Although an ontogenic study of V1b receptor binding is yet to be published, our recent work suggests that receptor expression does not play a role to this extent. In fact, both mRNA and protein levels of the AVP V1b receptor decrease with advancing gestational age (12). One might also argue that these changes simply reflect differences in the overall number or percentage of corticotropes present in the pituitary at a given gestational age. However, work by Perez et al. (11) suggests that the percentage of corticotropes actually decreases with advancing gestational age. Therefore, the increased IP formation observed in cells isolated from 140-dGA fetuses in the present study cannot be ascribed to an increased percentage of corticotropes and likely reflects heightened sensitivity.

We cannot exclude the possibility that some of the IP3 generated after stimulation with AVP in the present study may have been caused by activation of this second messenger system in cells other than corticotropes. The secretion of TSH, FSH, and LH are mediated through activation of the IP3 pathway (26, 27). AVP has indeed been shown to elicit TSH secretion in vitro (28), however, there is evidence to suggest that any such TSH originates from AVP responsive cells in which both TSH and ACTH are colocalized (29).

Given that HPD of the fetal sheep prevents the otherwise normal increases in plasma cortisol and bioactive ACTH concentrations (12, 30, 31, 32, 33) and, furthermore, the transition of corticotropes from fetal to adult type (30), we speculated that the ontogenic changes in IP3 would be altered after this manipulation. Here we have shown that HPD does in fact prevent pituitary cells from becoming more responsive to AVP in terms of both second messenger formation and resultant ACTH output when assessed in vitro. Although there are certainly a number of explanations for this effect of HPD on pituitary responsiveness, results from several studies suggest involvement of cortisol or, more precisely, the lack of cortisol in HPD fetuses as the mediating factor. In vivo and in vitro experiments in rats assessing changes in pituitary AVP elicited IP formation after pretreatment with dexamethasone showed that dexamethasone treatment increased the responsiveness of both whole pituitaries and primary cultured pituitary cells in terms of IP formation after stimulation with AVP (21). Work conducted by Bilezikjian et al. (19) failed to find an effect of glucocorticoids on AVP elicited IP3 formation in vitro using adult rat pituitary cells. However, in this study all manipulations were performed in vitro, and the dexamethasone exposure time was far less than that used in the other study (i.e. 18 vs. 168 h). Results from other studies lend support to the current findings regarding ACTH secretion. For example, when the cortisol surge in fetal sheep was prevented by adrenalectomy at 120 dGA, pituitary cells subsequently isolated from near-term fetuses (range 138–146 dGA) were found to secrete significantly less ACTH after stimulation with AVP than cells from animals with intact adrenals and high cortisol levels (10). Further underlying the apparent importance of glucocorticoids in mediating pituitary responsiveness is the finding that AVP responsive cells isolated from fetuses infused with cortisol are better able to maintain ACTH secretion than CRF responsive cells (20).

Pituitary cells from HPD fetuses did not differ from those isolated from sham fetuses in terms of viability or total number. In a previous study we showed that the percentage of corticotropes is actually higher in HPD compared with sham pituitaries at 140 dGA (33). Therefore, we are confident in the present study that the percentage of corticotropes isolated from HPD pituitaries was at least equal to, if not greater than, the percentage from sham pituitaries and was, therefore, not a confounding influence on the results.

The work of Rabadan-Diehl and Aguilera (21) also suggests an explanation as to how the changes in IP formation may be mediated. In addition to assessing IP formation, they also examined several post-receptor components of the signal transduction cascade, including G protein (type Gq), PLC, and calcium channel expression after the dexamethasone pretreatment. Although PLC and calcium channel expression did not appear to change, G protein levels in pituitaries from rats treated with dexamethasone for 1 wk were significantly increased from control (21). This led the authors to conclude that the heightened G protein expression results in increased G protein-PLC coupling and consequent second message formation. Other studies have also shown that glucocorticoids possess the ability to regulate G protein expression in various tissues and cells types (34, 35, 36). With these findings in mind, it is possible that G protein expression in the fetal sheep pituitary increases with the increasing plasma cortisol concentrations in late gestation, increasing G protein-PLC coupling efficiency, formation of IP3, and overall corticotrope sensitivity to AVP. This possibility merits investigation in the future.

The argument that cortisol is driving the increase pituitary responsiveness to AVP may initially seem somewhat counterintuitive, given that glucocorticoids are generally known to inhibit ACTH secretion. However, the fact remains that plasma ACTH concentrations in late gestation fetal sheep increase despite the increasing plasma cortisol concentrations. Evidently a unique physiological/biochemical balance exists within the HPA axis at this time, allowing such a response to occur.

It has been previously reported that corticotropes become decreasingly responsive to CRF as gestation proceeds (10). Therefore, one might have expected in the present study that HPD, and the associated HPA axis maturational disruption, would have impeded this developmental decrease from occurring. This was not the case. In contrast to the effects of AVP-induced ACTH secretion, we found that CRF-induced ACTH secretion was minimal in cells from both sham and HPD fetuses. The explanation for this finding is unclear. It may be that extra HPA axis factors mediate the maturational changes in pituitary responsiveness to CRF.

To our knowledge this is the first investigation to examine the importance of second messenger generation with regard to AVP signal transduction in the fetal sheep pituitary. It has previously been noted that ACTH responsiveness to AVP increases with advancing gestational age, but the underlying mechanism(s) have remained unclear. The findings from our study suggest that as gestation in the fetal sheep proceeds, the formation of IP3 after stimulation with AVP in pituitary cells increases. Furthermore, our findings from HPD fetuses indicate that this ontogenic change in second messenger formation requires an intact HPA axis and may be driven at least in part by increasing plasma cortisol concentrations.


   Footnotes
 
This research was supported by National Institutes of Health Grant HD11210. L.C.C. is supported by the RJR Leon-Golberg Fellowship in Pharmacology and Toxicology.

Disclosure Statement: The authors have nothing to disclose.

First Published Online November 30, 2006

Abbreviations: AVP, Arginine vasopressin; CRF, corticotropin releasing factor; dGA, d gestational age; HPA, hypothalamic-pituitary-adrenal; HPD, hypothalamo-pituitary disconnection; IP3, inositol trisphosphate; PLC, phospholipase C.

Received August 29, 2006.

Accepted for publication November 17, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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L. C. Carey, S. B. Tatter, and J. C. Rose
Cortisol infusion in late-gestation hypothalamo-pituitary disconnected sheep fetus restores pituitary cell responsiveness to arginine vasopressin
Am J Physiol Endocrinol Metab, February 1, 2009; 296(2): E300 - E304.
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