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Regular article |
During the Early Bovine Luteal Phase Does Not Alter the Expression of ET-1 and of Its Type A Receptor: A Possible Cause for Corpus Luteum Refractoriness
a Department of Animal Science, Faculty of Agriculture, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot 76100, Israel
b Department of Animal Science, Obihiro University of Agriculture & Veterinary Medicine, Obihiro 080-8555, Japan
ABSTRACT
Luteal regression is initiated by prostaglandin F2
(PGF2). In domestic species and primates, demise of the corpus luteum (CL) enables development of a new preovulatory follicle. However, during early stages of the cycle, which are characterized by massive neovascularization, the CL is refractory to PGF2. Our previous studies showed that endothelin-1 (ET-1), which is produced by the endothelial cells lining these blood vessels, plays a crucial role during PGF2-induced luteolysis. Therefore, in this study, we compared the effects of PGF2 administered at the early and mid luteal phases on ET-1 and its type A receptors (ETA-R) along with plasma ET-1 and progesterone concentrations, and the mRNA levels of PGF2 receptors (PGF2-R) and steroidogenic genes. As expected, ET-1 and ETA-R mRNA levels were markedly induced in midcycle CL exposed to luteolytic dose of PGF2 analogue (Cloprostenol). In contrast, neither ET-1 mRNA nor its receptors were elevated when the same dose of PGF2 analogue was administered on Day 4 of the cycle. In accordance with ET-1 expression within the CL, plasma ET-1 concentrations were significantly elevated 24 h after PGF2 injection only on Day 10 of the cycle. The steroidogenic capacity of the CL (plasma progesterone as well as the mRNA levels of steroidogenic acute regulatory protein and cytochrome P450scc) was only affected when PGF2 was administered during midcycle. Nevertheless, PGF2 elicited certain responses in the early CL: progesterone and oxytocin secretion were elevated, and PGF2-R was transiently affected. Such effects probably result from PGF2 acting on luteal steroidogenic cells. These findings may suggest, however, that the cell type mediating the luteolytic actions of PGF2, possibly the endothelium, could yet be nonresponsive during the early luteal phase.
corpus luteum, corpus luteum function, gene regulation
INTRODUCTION
The corpus luteum (CL) is a transient endocrine gland, and if no fertilization occurs, the CL will regress so that a new follicle may ovulate [1]. In domestic animals, CL regression is set in motion by the uterine secretion of prostaglandin F2 (PGF2) [2, 3]. Initially, progesterone secretion is inhibited, and during later stages, the gland undergoes structural luteolysis involving apoptotic cell death [4, 5]. The decline in the steroidogenic activity is accomplished within a few hours [5, 6] and appears to be achieved by reduced expression of steroidogenic acute regulatory protein (StAR) [7–10]. In addition to changes in steroidogenesis, PGF2-induced luteolysis is accompanied in ruminants by down-regulation of its own receptor (PGF2-R) [4, 11].
One of the enigmatic phenomenon characterizing the action of PGF2 is its inability to induce luteolysis during early stages of the reproductive cycle, which is referred to as CL refractoriness or insensitivity. For example, luteolysis cannot be initiated before Day 5 of the cycle in the cow [12, 13], before Day 8 of the cycle in the marmoset monkey, and before Day 4 of pregnancy in the pregnant rat [14, 15].
Our previous studies suggested that endothelin-1 (ET-1), which is a 21-amino-acid peptide, acts as a mediator of PGF2-induced luteal regression [16]. Its levels (both mRNA and peptide) were elevated within less than 2 h after in vivo or in vitro treatment with PGF2 [17, 18]. High concentrations of ET-1 can inhibit progesterone production by luteal cells, as has been demonstrated for several species, including the cow, sheep, and human [16, 19–21], suggesting a widespread role for ET-1 in luteolysis.
The inhibitory effects of ET-1 were exerted via the selective ETA (type A)-binding sites [19]. ETA receptor (ETA-R) mRNA levels were highest during luteal regression; moreover, an inverse relationship between ETA-R gene expression and progesterone production was detected [22], further supporting an inhibitory role of ET-1 in CL function. The present study examined involvement of ET-1 biosynthesis and responses in the refractory period of the bovine CL. We compared the effects of PGF2 administered during early and mid luteal phases on plasma ET-1 and progesterone concentrations and on the mRNA levels of ET-1, ETA-R, PGF2-R, and cyclo-oxygenase 2 (COX-2) along with genes related to steroidogenesis, including StAR and cytochrome P450 side-chain cleavage (P450scc).
MATERIALS AND METHODS
Materials
Dulbecco's minimum essential medium (DMEM) with Ham's F12 1:1 (v/v) nutrient mixture and SuperScriptII RNase H- Reverse Transcriptase were from Gibco BRL Life Technologies (Gaithersburg, MD). Deoxynucleotide triphosphates, random hexamer oligodeoxynucleotides, and Taq DNA polymerase were from Farmentas (Vilnius, Lithuania); oligo dT and oligonucleotide primers were synthesized by Biotechnology General (Kiryat Weizmann, Rehovot, Israel). The PGF2 analogue (Cloprostenol-Estrumate) was from Coopers (Berkhamsted, England). The controlled intravaginal drug-releasing device (CIDR) containing progesterone was from Erzi Breed (Hamilton, New Zealand). The Sep-Pak C18 cartridges were from Waters (Milford, MA). Bovine LH (USDA bLH-B-5) was kindly provided through the U.S. Department of Agriculture's animal hormone program (USDA; Beltsville, MD). PGF2 was purchased from Sigma Chemical Co. (St. Louis, MO).
Animals
Holstein dairy cows exhibiting regular cycles were utilized. The estrous cycles were synchronized by progesterone and PGF2. The CIDR was inserted for 9 days, and 500 g of Cloprostenol, a PGF2 analogue (PGF2-A) was injected i.m. 7 days after insertion of the CIDR. Cows expressing estrous behavior within 48 h of CIDR removal were included in these experiments. Day 0 was the day of behavioral estrus. All animal studies described in this study were reviewed and approved by the appropriate institutional animal care and use committee.
Experiment 1:
Plasma sampling. Five hundred micrograms of PGF2-A were administered i.m. on Day 4 (n = 4) or Day 10 (n = 4) of the bovine estrous cycle. Blood samples were collected from the jugular vein into heparinized vacutainers at 0, 1.5, 3, 4.5, 7, 14, 24, 31, 38, 48, 55, and 62 h after injection. Plasma was stored at -20°C until assayed.
Experiment 2:
CL collection. PGF2-A was administered i.m. to cows during the early luteal phase (Days 2–4), and CL was collected 4 h (n = 6) and 24 h (n = 8) later. Cows at the mid luteal phase (Days 7–14) were injected with PGF2-A, and CL was collected 4 h (n = 4), 7 h (n = 4), and 24 h (n = 4) later. Gene expression in CL was only measured to 24 h after PGF2-A injection, because at time-points beyond the initial 24 h, the tissue undergoes apoptosis and the quality of the RNA extracted may deteriorate. Control groups were comprised of CL collected randomly from untreated cows at either the early (Days 2–4; n = 8) or mid (Days 7–14; n = 8) luteal phase. All CL samples were snap frozen in liquid nitrogen and stored at -70°C until RNA extraction.
CL Incubations
Corpora lutea were sliced and incubated as described elsewhere [19]. Briefly, CL were washed, sliced, and cultured in a 96-well plate (one slice/well). Slices were preincubated in DMEM with Hepes and 5% fetal calf serum, and media were replaced every 30 min for 2 h at 37.5°C. Slices were than incubated under gentle shaking with the hormonal treatments for an additional 5 h. At the end of the incubation period, the weight of the slices was recorded, and the media were collected.
Semiquantitative Reverse Transcriptase-Polymerase Chain Reaction
Total RNA was extracted from tissues by the guanidinium thiocyanate method. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was performed as described elsewhere [22–24], with the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (G3PDH) used as an internal standard. The housekeeping gene G3PDH is constitutively expressed in both granulosa-derived luteal cells and theca-derived luteal cells, and it has been used effectively in studies concerning the regulation of gene expression in ovarian cells [22–24]. The sequence of the primers used is shown in Table 1.
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To avoid coamplification of related genes (i.e., prostaglandin E2 receptor, ETB receptor, COX-1, and ET-2 and -3), the primers were designed at regions having low homology to these related genes. The identity of the PCR products was ascertained use of sequence analysis or restriction enzymes. The number of cycles was varied to determine the optimal number that would allow detection of the appropriate mRNA transcripts while keeping amplification for these genes in the log phase, as we have previously described (primer dropping method) [25]. Amplification cycles used in these PCR reactions were: G3PDH, P450scc, StAR, and PGF2-R, 20 cycles; ETA-R, 24 cycles; ET-1, 25 cycles; and COX-2, 30 cycles.
Computer searches and sequence alignments were performed using software from Genetics Computer Group, Inc. (Madison, WI).
Determination of ET-1 and Progesterone in Plasma Samples
Progesterone and ET-1 concentrations in plasma were determined with double-antibody enzyme immunoassays [18, 21]. Progesterone concentrations were assayed after extraction by diethylether. The standard curve ranged from 0.05 to 50 ng/ml, and the ED50 of the assay was 1.8 ng/ml. Extraction of ET-1 from serum was performed by diluting 3 ml of plasma with 3 ml of distilled water, adjusting the pH to 2.5 with 5 M HCl, and applying to Sep-Pak C18 cartridge as described elsewhere [18]. Samples were concentrated 25-fold as a result of the process. Values of the measured ET-1 concentrations were corrected for recovery loss (recovery - 56% ± 3.0%, which was determined using synthetic ET-1 added to plasma). The standard curve for ET-1 ranged from 9.7 to 5000 pg/ml. The ED50 of the assay was 450 pg/ml. Cross-reactivities of ET-1 antiserum with ET-1, ET-2, ET-3, and big endothelin (aa 38) were 100%, 50%, 22% and 3%, respectively.
Statistical Analysis
Data are presented as mean ± SEM. Statistical analysis was performed using the JMP package (Version 3.2; SAS Institute, Cary, NC). One-way ANOVA was used to determine the statistical significance of individual treatments, as indicated in the text. The statistical model included stage of cycle (early vs. mid luteal phase), time (after PGF2 injection), and their interactions. The difference between groups (P value) was determined using Dunnett test.
RESULTS
Effect of PGF2-A on Plasma Progesterone and ET-1 Concentrations
Profiles of plasma progesterone before and after administration of PGF2-A on Day 4 or 10 of the cycle are shown in Figure 1. The mean preinjection values of progesterone concentrations in plasma were typical for Day 4 and 10 of the bovine estrous cycle. In contrast to the well-documented fall (becoming statistically significant from 4 h after PGF2) in progesterone occurring after PGF2-A injection during midcycle, a gradual increase in plasma progesterone concentrations was found on Day 4, becoming statistically significant from 36 h after PGF2 (Fig. 1). This pattern characterizes a developing CL and confirms a lack of PGF2-induced luteal regression at this stage of the cycle.
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Concentrations of ET-1 in plasma samples (before and at 4.5 h after PGF2-A injection) were not statistically different between cows on Days 4 and 10 of the cycle (Fig. 2). The mean concentrations of ET-1 after injection of PGF2 in cows on Day 4 was significantly lower than that in cows injected on Day 10 of the cycle (5.84 ± 0.27 and 7.42 ± 0.28 pg/ml; P < 0.001 and 0.01, respectively).
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Effect of PGF2-A on Luteal ET-1 and ETA-R mRNA Levels
The increased concentration of ET-1 in plasma samples reflected its mRNA expression within the CL (Fig. 3). As expected from our previous studies [17, 18], a luteolytic dose of PGF2-A administered to cows at midcycle increased luteal ET-1 mRNA in a time-dependent manner (Fig. 3). After 24 h, levels reached values that were sixfold higher than those in the CL of noninjected cows.
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In addition, PGF2 up-regulated ETA-R mRNA levels at this stage, although an increase was evident only 24 h after PGF2 (Fig. 3). However, no increase was observed in either ET-1 or ETA-R mRNA levels when the same dose of PGF2-A was administered on Day 4 of the cycle, and amounts of ET-1 and ETA-R mRNA remained constant for as long as 24 h after PGF2 (Fig. 3).
Effect of PGF2-A on Luteal Gene Expression
We next determined the mRNA expression of other genes that may be altered during the course of luteal regression (Fig. 4).
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On Day 10, injection of PGF2-A reduced the expression of StAR and P450scc genes, and 24 h later, their levels were reduced to 10% and 20% of that observed in nontreated cows (Fig. 4). At shorter time-points, StAR showed a tendency to be more rapidly reduced than P450scc mRNA; however, this effect was not statistically significant (P < 0.08). The COX-2 mRNA had a unique pattern of expression, being transiently increased by 11-folds (P < 0.01) at 4 h and decreasing rapidly thereafter (Fig. 4). None of these genes was affected by injection of PGF2-A on Day 4 of the cycle.
The PGF2-R mRNA levels were initially decreased at 4 and 7 h after treatment for the early and mid luteal phase CL, respectively. However, at midcycle, these levels remained low at 24 h after PGF2, whereas at the early cycle, PGF2-R mRNA levels recovered and were similar at 24 h to those of nontreated controls (Fig. 4).
The temporal effects of PGF2 on the various genes examined were significantly different in the mid luteal phase compared with the early luteal phase CL. A significant statistical interaction was found between time and luteal stage, with P < 0.001, 0.03, 0.003, 0.02, 0.001, and 0.001 for the mRNA levels of ET-1, ETA-R, StAR, P450scc, PGF2-R, and COX-2, respectively.
In Vitro Effects of PGF2 on Early Luteal Phase CL
The amounts of progesterone secreted from immature CL slices on Days 2–4 of the cycle are shown in Table 2. Both PGF2 (1 µg/ml) and LH (100 ng/ml) significantly increased progesterone secretion to values approximately twofold higher than those of controls. Incubation with LH and PGF2 did not alter progesterone secretion in these young CL slices relative to that of LH (Table 2). In addition to its effect on progesterone, PGF2 augments oxytocin release from midcycle CL [6, 18]. Therefore, we examined its effect on oxytocin production during the early luteal phase as well. Using 4-day-old CL slices in an in vitro microdialysis system [26], PGF2 also significantly (P > 0.05) increased oxytocin release by 138.7% ± 6.4% compared with controls (14.2 ± 0.9 and 10.2 ± 1.1 pg/ml; PGF2 vs. control, respectively).
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DISCUSSION
Luteal regression is a key process in reproduction. It controls the length of the reproductive cycle, and it regulates the establishment and maintenance of pregnancy. Nevertheless, many gaps remain in our understanding of the mechanisms regulating luteolysis. One aspect that has drawn interest in recent years is the refractoriness of the CL during the early stages of its development to the luteolytic actions of PGF2. This study provides evidence suggesting that lack of ET-1 production in the young CL may be involved in this phenomenon. Neither ET-1 nor ETA-R mRNA were elevated when a luteolytic dose of PGF2-A was administered on Day 4 of the cycle. This contrasts sharply with the abrupt induction in both genes observed at midcycle, both in this study and in other [17, 22]. Previous studies showed that during natural or PGF2-induced luteolysis, not only ET-1 mRNA but also the peptide content of the gland was markedly elevated, and that its peptide concentrations within the CL rose three- to fivefold 24 h after PGF2 [18]. A peptide with a short half-life, ET-1 acts in a paracrine/autocrine manners [27, 28]; therefore, its levels in the circulation normally are low [29]. Nevertheless, under certain conditions, such as in congestive heart failure [29, 30], plasma levels of ET-1 do rise. Findings in this study suggest that luteal regression may be another situation in which plasma ET-1 levels rise. That plasma ET-1 concentrations were only elevated when PGF2-A was injected at Day 10 of the cycle further supports the findings that before Day 5, PGF2 failed to increase ET-1 expression in the CL.
A premature elevation in PGF2 (on Day 5 of the cycle) was previously suggested [31] as being a cause for short cycles in cows. The inability of PGF2 to induce luteolysis during this stage of the cycle raises the question of whether other intraluteal factors play a more significant role in short-lived CL.
Levels of PGF2-R in the bovine CL are already present early in the cycle [22, 32]. The early luteal phase CL not only expresses receptors for PGF2 but this prostaglandin can induce specific responses [33, 34]. The findings reported here agree with those of previous studies: the young CL responded to exogenous PGF2 with alterations in PGF2-R mRNA levels, progesterone, and oxytocin production. However, if the early CL responds to PGF2 why is it resistant to its luteolytic actions? Tsai and Wiltbank [33] claimed that PGF2-R, as such, cannot account for the refractoriness of the early CL to PGF2, because these receptors are already present in the gland on Day 2 of the cycle. However, when trying to answer this intriguing question, it may be necessary to consider the various luteal cell types that express PGF2-R and respond to PGF2 [23]. Thus, the levels of mRNA present in whole tissue do not necessarily represent the levels present in the various cell types. Moreover, receptors sometimes are expressed at higher amounts in certain cell types, which might mask changes occurring in other cell types.
The responses to PGF2 in the young CL observed both by others [33, 34] and in this report are exerted on steroidogenic cells. This seems to be obvious when considering the effects on 3ß-hydroxy steroid dehydrogenase [33], progesterone, and oxytocin productions [34]; however, it is also true for PGF2-R. In a previous study, we showed that PGF2 can directly act on luteal steroidogenic cells to decrease the expression of its own receptor [23]. In fact, PGF2-R is up-regulated in follicular cells (i.e., the progenitors of luteal steroidogenic cells) after the LH surge [35] or cAMP activation [23]. Taken together, these observations clearly indicate that the early differentiating steroidogenic luteal cells (on Days 1–5 of the bovine cycle) contain PGF2-R and, therefore, can respond to PGF2. However, at this early stage of development, the neovascularization has not yet been completed [36, 37], and the endothelial cells lining the newly formed blood vessels are still dividing and differentiating. Endothelial cells of the mature CL contain the receptors for PGF2 and are the main source of ET-1, the expression of which increases in response to PGF2 in the CL [17]. Therefore, a likely explanation for the insensitivity of CL is that the cell type mediating the luteolytic actions of PGF2, possibly the endothelium, is still nonresponsive. Paucity of endothelial cells per se and/or their inability to respond to PGF2 before Day 5 may cause the refractory state. Nonetheless, direct proof for this contention is still missing and awaits further research.
Administration of PGF2 elevated COX-2, which is the rate-limiting enzyme in prostaglandin synthesis, at the mid but not at the early luteal phase [33]. Because ET-1 (elevated only at midcycle) is a potential inducer of this enzyme in endothelial and other cell types [38, 39], it may provide additional support for the crucial role of the endothelium/ET-1 in luteal regression. That endothelial cells are the main cell type undergoing apoptotic cell death during luteolysis [37, 40] is also consistent with this conclusion.
It has been widely documented in recent years that PGF2-induced luteolysis involves reduction in StAR mRNA and protein levels of the CL. This has been demonstrated in ovine [8], bovine [9], rat [10], and human [7] CL. In contrast to midcycle CL, injection of PGF2 on Day 4 did not decrease StAR mRNA levels and plasma progesterone concentrations [33]. Because at this stage of the cycle PGF2 also failed to induce the expression of ET-1, these two events may be related. This concept is supported by our previous finding that ET-1 acts on luteal cells to inhibit basal and cAMP-induced steroidogenesis in several species [16, 19, 20]. In addition, after injection of PGF2, luteal progesterone decreases concurrently with the increase in ET-1 [18]. The time frame of these in vivo and in vitro inhibitory effects of ET-1 was in accord with the acute effects induced by StAR.
The data in this study suggest that lack of ET-1 synthesis and response at the early luteal phase may render the CL refractory to the luteolytic action of PGF2. These data add to the accumulating body of literature portraying ET-1 as a key player in PGF2-induced luteal regression.
ACKNOWLEDGMENTS
We would like to express our deep gratitude to Dr. G. Brener and the employees of Marbek abattoir. To Mr. N. Shani from Kibbut Zikim, Mr. M. Ramon from Kibbutz Grofit, the team at the "Golan" dairy herd, and Mr. U. Mualem, manager of the experimental dairy farm of ARO Institute. This work could not have been accomplished without their cooperation.
FOOTNOTES
First decision: 12 November 1999.
1 Correspondence. FAX: 972 8 9465763; rina{at}agri.huji.ac.il 
Accepted: March 9, 2000.
Received: October 11, 1999.
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