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Regular Article |
-Induced Luteal Regression in the Ewe
a Department of Animal Science, University of Connecticut, Storrs, Connecticut 06269-4040
ABSTRACT
A diversified series of experiments was conducted to determine the potential role of endothelin-1 (ET-1) in ovine luteal function. Endothelin-1 inhibited basal and LH-stimulated progesterone production by dispersed ovine luteal cells during a 2-h incubation. This inhibition was removed when cells were preincubated with cyclo-D-Asp-Pro-D-Val-Leu-D-Trp (BQ123), a highly specific endothelin ETA receptor antagonist. Administration of a luteolytic dose of prostaglandin F2
(PGF2) rapidly stimulated gene expression for ET-1 in ovine corpora lutea (CL) collected at midcycle. Intraluteal administration of a single dose of BQ123 to ewes on Day 8 or 9 of the estrous cycle mitigated the luteolytic effect of PGF2. Intramuscular administration of 100 µg ET-1 to ewes at midcycle reduced plasma progesterone concentrations for the remainder of the estrous cycle. Following pretreatment with a subluteolytic dose of PGF2, i.m. administration of 100 µg ET-1 caused a rapid decline in plasma progesterone and shortened the length of the estrous cycle. These data complement and extend previously published reports in the bovine CL and are the strongest evidence presented to date in support of a role for ET-1 in PGF2-mediated luteal function in domestic ruminants.
corpus luteum, corpus luteum function, progesterone
INTRODUCTION
Endothelin-1 (ET-1), a 21-amino acid peptide produced and released by endothelial cells, was first isolated and characterized from cultured porcine aortic endothelial cells in 1988 [1]. Endothelin-1 is a member of a family of structurally related peptides that includes ET-2, ET-3, and sarafotoxins [2]. Endothelin-1 is the most potent vasoconstrictor yet identified and exerts a wide spectrum of biological effects in different tissues [3]. Endothelin-1 has been identified in the bovine corpus luteum (CL) in which the content varied throughout the estrous cycle with highest concentrations of peptide and mRNA present during luteal regression [4]. Recent studies in heifers suggest that ET-1 may play a role in prostaglandin F2 (PGF2)-induced luteal regression. Prostaglandin F2 stimulated the biosynthesis of ET-1 in a number of systems studied, including cultured bovine luteal endothelial cells [4], luteal slices [5], microdialyzed luteal tissue [6], and bovine CL in vivo [7]. Additionally, PGF2 caused a rapid stimulation of gene expression for ET-1 in cultured luteal endothelial cells and in luteal tissue [4–5]. Endothelin-1 has also been shown to act via high-affinity ETA binding sites to decrease progesterone production by dispersed bovine luteal cells. This effect was removed when the cells were preincubated with a highly specific ETA receptor antagonist [5]. Infusion of microdialyzed bovine luteal tissue with ET-1 inhibited the release of progesterone by that tissue, whereas exposure of microdialyzed luteal tissue to PGF2 prior to the infusion of ET-1 intensified the inhibitory effect of ET-1 on progesterone release [6].
A series of experiments employing diversified techniques was carried out in order to obtain basic information about the potential regulatory role of ET-1 in ovine luteal function. The following specific objectives were examined in these studies: 1) determination of the effects of ET-1 on progesterone production by dispersed ovine luteal cells; 2) determination of the gene expression of luteal ET-1 during the estrous cycle and after administration of a luteolytic dose of PGF2; 3) determination of the effect of intraluteal administration of a specific ETA receptor antagonist prior to administration of a luteolytic dose of PGF2 on plasma concentrations of progesterone in vivo; and 4) determination of the effect of an i.m. injection of ET-1 alone and following pretreatment with a subluteolytic dose of PGF2 on concentrations of plasma progesterone and estrous cycle lengths.
MATERIALS AND METHODS
Animals and Surgery
Normally cycling Dorset, Shropshire, and crossbred ewes maintained at the University of Connecticut Beef and Sheep Center were randomly assigned for use in all experiments. Ewes had ad libitum access to pasture and water and were fed supplemental hay and silage as needed. Ewes were observed for estrus daily in the presence of a vasectomized ram fitted with a marker harness. The day of estrus was designated as Day 0. Ewes were subjected to flank laparotomy under local anesthesia (2% lidocaine) for removal of CL on appropriate days of the cycle and for intraluteal injection of the ETA antagonist cyclo-D-Asp-Pro-D-Val-Leu-D-Trp (BQ123; Sigma, St. Louis, MO). PGF2 (Lutalyse; Upjohn Co., Kalamazoo, MI) and ET-1 were administered i.m. via 27-gauge needle and Hamilton syringe (Hamilton Scientific, Reno, NV). Each ewe received 5 ml penicillin i.m. (300 000 units/ml) prior to surgery and for 5 days following surgery. All procedures involving animals were conducted according to protocols approved by the University of Connecticut Institutional Animal Care and Use Committee.
Reagents
Ovine LH (NIADDK-oLH-25 AFP 5551B) was provided by NIADDK-NIH. Endothelin-1 (human, porcine) was purchased from Sigma. [1,2,6,7-3H]Progesterone and [32P]dCTP were purchased from New England Nuclear (Boston, MA). Collagenase was obtained from Worthington Biochemical (Freehold, NJ). Medium 199 (M199) was purchased from Gibco (Grand Island, NY). Trizol reagent and random priming DNA-labeling kit were purchased from Gibco-BRL (Gaithersburg, MD). Lidocaine and penicillin were purchased from J.A. Webster (Sterling, MA).
Luteal Cell Incubations
Corpora lutea were collected from normally cycling ewes (n = 9) on Day 8 of the estrous cycle via flank laparotomy under local anesthesia. Total luteal tissue per animal was pooled and dispersed with collagenase (12.5 mg/g/ml). Treatments of 0, 10, 100, and 1000 ng ET-1 in 10 µl of M199 were added to 1-ml aliquots of cells in plastic tubes (55 x 12 mm; Sarstedt, Newton, NC) in triplicate (0.25–0.5 x 105 cells/ml) in the presence and absence of 100 ng oLH. Cells obtained from three animals were preincubated with 100 µg BQ123 in 10 µl M199 for 20 min prior to the addition of oLH and 100 or 1000 ng ET-1. After a 2-h incubation at 37°C under 5% CO2, cells in medium were frozen for subsequent determination of progesterone production by RIA according to a previously published method [8].
RNA Extraction and Northern Hybridization
Corpora lutea (n = 3/time point) were collected via flank laparotomy under local anesthesia on Days 5, 8, and 13 of the estrous cycle and 4 and 12 h after administration of 10 mg PGF2 on Day 8. Tissue collected for RNA analysis was frozen on CO2 immediately after removal and stored at -80°C. Total RNA was extracted using Trizol reagent according to the manufacturer's recommendations. Equal amounts of RNA (40 µg) from all samples were loaded onto an agarose gel (10 g/L, 0.66 mol/L formaldehyde) and simultaneously subjected to electrophoresis. A Posiblot apparatus (Stratagene, La Jolla, CA) was used to transfer RNA to a Gene Screen Plus membrane (DuPont, New England Nuclear). After ultraviolet crosslinking, the membrane was hybridized with 32P-labeled bovine ET-1 probe (generous gift of Dr. P. Marsden, Department of Medicine, St. Michael's Hospital, Toronto, Canada). Labeled cDNA probe was prepared by synthesizing complementary strands of DNA using a random primer DNA labeling kit (Gibco-BRL) and was purified by passing through a Nuc-Trap (Stratagene) minicolumn. Hybridization was carried out at 42°C overnight. The membrane was stripped and probed a second time with a 32P-labeled 1.6-kilobase fragment of the ribosomal protein rpl32 cDNA (generous gift of Dr. M. McGrane, Department of Nutritional Sciences, University of Connecticut) in order to assay total RNA loading per lane. The single membrane was exposed to Kodak XAR-5 film at -80°C after each hybridization. Autoradiograms were quantified by scanning with a Bio-Rad model GS-670 imaging densitometer. The resulting images were analyzed using Molecular Analyst software (Bio-Rad, Melville, NY).
In Vivo Treatments
Ewes were randomly assigned to receive intraluteal injections of either 100 µl saline (n = 5) or 100 µg BQ123 in 100 µl saline (n = 4) 30 min prior to i.m. administration of 10 mg Lutalyse on Day 8 or 9 of the estrous cycle. The number of CL present on each ovary was determined by gentle manual palpation, and each CL per animal was injected with the appropriate solution. Only animals with one or two palpable CL were used. Jugular venous blood was collected prior to intraluteal injection of BQ123 or saline, 30 min later at the time of Lutalyse administration, and at 0.5, 1, 2, 4, 6, 8, 12, and 24 h thereafter.
In a second experiment, ewes (n = 3 per treatment group) were randomly assigned to receive one of four i.m. treatments on Day 8 or 9 of the estrous cycle: 200 µl saline (SAL), 100 µg ET-1 in 200 µl saline (ET-1), 7.5 mg Lutalyse (PGF2), or 100 µg ET-1 15 min after administration of a subluteolytic dose (7.5 mg) of Lutalyse (PGF2/ET-1). On the day of treatment each ewe was fitted with an indwelling jugular catheter (Abbott Laboratories, Chicago, IL). Jugular venous blood was collected prior to treatment and at intervals of 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, and 24 h after treatment, and then daily until each animal returned to estrus.
Radioimmunoassays
Plasma concentrations of progesterone and progesterone production in medium plus cells were quantified by RIA as previously described [8].
Statistical Analysis
Data obtained from the dispersed luteal cell experiments and Northern analysis experiments were submitted to one-way ANOVA followed by mean separation tests (least significant difference) where a significant F value was obtained. Data obtained from experiments conducted in vivo were analyzed using the general linear model (GLM) procedure of Statistical Analysis System (SAS). When appropriate, differences between treatment means were further evaluated by least squares difference using the PDIFF command in the GLM subroutine of SAS [9].
RESULTS
Effect of ET-1 on Progesterone Production by Dispersed Luteal Cells
Total weight of luteal tissue collected per ewe varied widely between ewes (0.43–1.1 g) as did absolute concentrations of progesterone production over the 2-h incubation period (2.3–>60 ng/ml). Consequently, basal and oLH-stimulated progesterone production by cells untreated with ET-1 from each animal after the 2-h incubation were considered as baseline production (100%). Results for this study are reported as proportion of baseline. The addition of 100 and 1000 ng ET-1 caused a reduction in basal progesterone production (66.7 ± 5.5% and 64.7 ± 5.0%, respectively, P < 0.01), whereas the addition of 10 ng ET-1 had no effect on basal progesterone production (89.9 ± 6.1%) as compared to baseline control incubations (Fig. 1). The addition of 10 and 1000 ng ET-1 inhibited LH-stimulated progesterone production as compared to progesterone production by cells treated with oLH alone (79.2 ± 5.2% and 78.8 ± 6.7%, P < 0.05). The addition of 100 ng ET-1 resulted in a nonstatistically significant reduction of oLH-stimulated progesterone production (86.6 ± 8.0%). Preincubation with BQ123 reversed the inhibitory effects of ET-1 on basal and oLH-stimulated progesterone production. Basal progesterone levels were 104 ± 7.5% and 115.9 ± 16.3%, respectively, as compared to levels in untreated control incubations. Following preincubation with BQ123 the addition of 1000 ng ET-1 had no effect on LH-stimulated progesterone production (95.6 ± 13.7%) (Fig. 1).
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Northern Analysis of Luteal ET-1 mRNA Expression
The amount of ET-1-specific RNA detected by densitometric analysis of Northern blots in tissue collected 4 and 12 h after an injection of 10 mg Lutalyse on Day 8 of the estrous cycle was higher (2.4- and 2.7-fold) than that of untreated control animals (P < 0.05) (Fig. 2). There was no significant difference in gene expression for ET-1 in ovine luteal tissue collected on Days 5, 8, or 13 of the estrous cycle.
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Effect of Intraluteal Pretreatment with BQ123 on PGF2-Induced Luteolysis In Vivo
Intraluteal injection of 100 µg BQ123 30 min prior to i.m. injection of 10 mg Lutalyse mitigated the luteolytic effect of PGF2 as compared to pretreatment with saline (P < 0.01). Plasma progesterone concentrations in ewes pretreated with BQ123 were higher (P < 0.05) than those of saline-treated ewes at 1 h (3.0 ± 0.3 vs. 2.5 ± 0.2 ng/ml), 4 h (2.25 ± 0.2 vs. 1.9 ± 0.3 ng/ml), 6 h (2.2 ± 0.4 vs. 1.4 + 0.1 ng/ml), 8 h (2.3 + 0.2 vs. 1.4 ± 0.2 ng/ml), 12 h (2.1 ± 0.5 vs. 1.3 ± 0.2 ng/ml), and 24 h (0.99 ± 0.04 vs. 0.3 ± 0.03 ng/ml) after administration of exogenous PGF2. There were no differences in mean plasma progesterone concentrations in BQ123- versus saline-treated ewes prior to treatment (4.2 ± 0.4 vs. 4.1 ± 0.3 ng/ml), at the time of PGF2 administration (3.3 ± 0.6 vs. 3.3 ± 0.5 ng/ml), 30 min after PGF2 (3.1 ± 0.3 vs. 3.1 ± 0.3 ng/ml), or 2 h after PGF2 (2.4 ± 0.04 vs. 2.5 ± 0.2 ng/ml) (Fig. 3).
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Effect of ET-1 Alone and Following Pretreatment with PGF2 on Luteal Function In Vivo
Administration of 100 µg ET-1 in 200 µl saline resulted in an increase in concentrations of plasma progesterone (6.3 vs. 4.1 ± 0.5 ng/ml, P < 0.01) 4 h after treatment and decreased concentrations of progesterone in plasma from 24 h after treatment for the remainder of the study (P < 0.05) as compared to plasma from animals that received SAL. Prostaglandin F2 treatment resulted in a transient decline in progesterone concentrations in plasma 8–12 h after treatment (P < 0.05) followed by a return to levels similar to the SAL group through the remainder of the study. Ewes that received PGF2/ET-1 treatment showed a rapid decline in plasma progesterone levels (P < 0.01) and returned to estrus 60–72 h after treatment (Fig. 4). Estrous cycle length for the PGF2/ET-1 group was shortened (10.3 ± 0.5 days, P < 0.01) as compared to SAL (16.3 ± 1 days), ET-1 (16.3 ± 0.5 days), and PGF2 (16 ± 0 days) treatments.
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DISCUSSION
While the role of ET-1 in bovine luteal function is strongly suggested by recent studies [4–7], this is the first study directly designed to examine the hypothesis that ET-1 plays a role in PGF2-induced luteal regression in the ewe. Endothelin-1 has been reported to alter steroidogenesis in ovarian [10, 11], testicular [12], and adrenal [13] systems. Because luteal regression is characterized by a decrease in progesterone secretion, the objective of the first experiment was to examine the effects of ET-1 on progesterone production in vitro. Incubation with ET-1 inhibited basal and oLH-stimulated progesterone production by dispersed ovine luteal cells collected on Day 8 after estrus. The inhibitory effects of ET-1 on basal progesterone production were more pronounced than the effects on LH-stimulated progesterone production. The addition of 100 ng ET-1 to aliquots of cells resulted in a nonstatistically significant reduction in oLH-stimulated progesterone production by those cells. Because small luteal cells are more responsive to the stimulatory effects of LH, these results may reflect differences in cell populations among the aliquots of dispersed cells. In a second experiment, cells from three animals were preincubated for 20 min with BQ123 prior to addition of ET-1. Preincubation with BQ123 removed the inhibitory effects of ET-1 on basal and gonadotropin-stimulated progesterone production. Although neither endothelin receptors nor receptor mRNA have been characterized in the ovine CL, the present results are in agreement with those observed in the bovine [5] and human [10] CL, indicating that the effects of ET-1 in ewes are probably mediated via ETA receptors.
A 2.4- and 2.7-fold increase in ET-1-specific mRNA was detected in ovine luteal tissue collected 4 and 12 h after administration of a luteolytic dose (10 mg Lutalyse) of PGF2 on Day 8 of the estrous cycle, indicating that gene expression of ET-1 was stimulated by exogenous PGF2 administered at midcycle. Although increased levels of ET-1-specific mRNA were present in bovine luteal tissue collected late in the estrous cycle [4], densitometric analysis revealed no difference in the amount of ET-1-specific mRNA detected at Day 5, 8, or 13 after estrus in ovine luteal tissue collected for this study. Plasma progesterone concentrations for the ewes from which luteal tissue was collected on Day 13 for this study ranged between 2 and 3 ng/ml, indicating that the ewes had not yet begun to undergo luteal regression. Ovine CL collected on Days 14–16 after estrus may reveal increased expression of ET-1 mRNA if functional regression has begun to occur. However, due to the proliferation of connective tissue late in the estrus cycle, ovine CL are difficult to collect at that time via flank laparotomy. Because of the low abundance of ET-1-specific mRNA in luteal tissue, future studies employing more sensitive molecular techniques may provide more reliable and quantifiable results in the ewe.
Intraluteal injection of 100 µg BQ123 in 100 µl saline to ewes 30 min prior to a luteolytic dose of PGF2 on Day 8 or 9 mitigated (P < 0.05) but did not completely block the luteolytic effect of PGF2 as compared to intraluteal administration of saline alone. The study described here is the first in which a selective ET-1 receptor antagonist was administered in vivo to ewes. In interpreting these results, the relative ability of receptor antagonists to bind to ET-1 receptors must be taken into account. Despite their selectivity, receptor antagonists such as BQ123 form a less stable and more reversible complex with the ETA receptor than does ET-1, leading to the idea that full-length ligands may interact with the receptor at multiple binding points [14, 15].
While the ETA receptor is clearly the predominant receptor type present in bovine luteal cells [5], the presence of a small number of ETB receptors may contribute to the incomplete blockage of the endothelin system observed here following intraluteal administration of BQ123. Additionally, Bird and Waldron [16] have shown in the conscious rat that the inhibition of ET-1-induced effects in arterial blood pressure by BQ123 exhibits a nonlinear, bell-shaped response curve. This suggests that the timing of administration of an ETA receptor antagonist prior to a luteolytic dose of PGF2 may critically influence the degree of antagonism attained. The data presented here were obtained with only a single injection of BQ123 per palpable CL per ewe. Further experiments designed to determine the optimal dose, timing, and mode of delivery of ETA receptor antagonists are warranted.
Intramuscular administration of 100 µg ET-1 in 200 µl saline to ewes on Day 8 or 9 of the estrous cycle had no effect on plasma progesterone concentrations during the first 2 h after administration. However, by 4 h, mean plasma progesterone concentrations had increased by 30% (P < 0.05). Following this peak of secretion, plasma progesterone declined from 24 h after treatment for the remainder of the estrous cycle and never regained levels that were similar to saline-treated controls. Ewes that received a subluteolytic dose of PGF2 had a small increase in plasma progesterone within 30 min of treatment. This was followed by a transient decline in progesterone concentrations 8–12 h after treatment. Similar effects following low doses of PGF2 have been documented by others [17] who also observed an increase in oxytocin secretion concomitant with the increase in progesterone. There was no difference in mean concentrations of plasma progesterone in the treatment group that received a subluteolytic dose of PGF2 as compared to those of saline-treated animals from 24 h after treatment to the end of the estrous cycle (P = 0.2).
Ewes that received 100 µg ET-1 preceded by a subluteolytic dose of PGF2 displayed a rapid decline in progesterone concentrations in plasma and returned to estrus 60–72 h after treatment. The success of this combination protocol in inducing rapid functional and structural luteolysis in ewes supports evidence presented in previously reported studies in the bovine CL [4–6] and is perhaps the strongest evidence in support of the role of ET-1 in mediating PGF2-induced luteal regression. As has been previously observed [6] in the bovine CL, pre-exposure to PGF2 intensified the inhibitory effect of ET-1 on progesterone secretion in microdialyzed tissue. This observation in conjunction with effects reported here suggest that endothelin receptors may require priming by PGF2.
The effect of administration of ET-1 alone, however, was powerful, and further study is warranted. Although injection of ET-1 alone did not induce luteolysis, a single injection of ET-1 administered systemically at midcycle increased concentrations of progesterone in plasma 4 h after treatment and then reduced (P < 0.05) mean concentrations of plasma progesterone by this group for the remainder of the cycle. Using an in vivo luteal microdialysis system Ohtani et al. [7] reported a tremendous release of intraluteal ET-1 (160% of baseline) and of oxytocin (960% of baseline) in cows 4 h after a luteolytic injection of a PGF2 analogue (500 µg closprostenol). Because ET-1 and its receptors are found in virtually every physiological system, the present results may represent an effect mediated other than directly at the ovarian level, such as at the hypothalamus or pituitary [18]. It is not known whether i.m. administration of ET-1 had a partially cytotoxic effect at the level of the CL.
In summary, the data reported here are the strongest evidence presented to date in support of a novel role for ET-1 in mediating PGF2-induced luteal regression and contribute to a growing body of knowledge suggesting a role for ET-1 in regulation of ruminant luteal function.
ACKNOWLEDGMENTS
The authors acknowledge the assistance offered by Dr. Mary M. McGrane of the Departments of Nutritional Sciences and Molecular and Cellular Biology, University of Connecticut. Expert technical assistance was provided by David T. Schreiber, Jr. and Shawn L. Lewis of the Department of Animal Science, and by Saritha Pasham of the Department of Nutritional Sciences.
FOOTNOTES
1 Supported by USDA grant no. 97-35203-4856. 
2 Correspondence: R.A. Milvae, Department of Animal Science, 3636 Horsebarn Rd. Extension, Storrs, CT 06269-4040. FAX: 860 486 4375; rmilvae{at}canr.uconn.edu
Accepted: January 11, 2001.
Received: June 5, 2000.
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