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and Endothelin-1 as a Local Luteolytic Factor in the Bovine Corpus Luteum In Vitro1
a Department of Animal Science, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(PGF2) and endothelin-1 (ET-1) in the bovine corpus luteum (CL) of the mid-luteal phase, by using an in vitro microdialysis system (MDS). Ang II was detected in the MDS perfusate (4 pg/ml), and infusion of PGF2 (10-6 M) for 2 h increased the Ang II release by 50–100% during the following experimental period, in addition to its stimulation of ET-1 release. Two 2-h infusions of Ang II (10-7-10-5 M) separated by a 2-h interval induced a dose- and time-dependent decrease of progesterone (P4) release by 41–66%. When the luteal explants were pre-perfused with PGF2 (10-6 M) for 2 h, two consecutive perfusions of Ang II (10-6 M) at a 2-h interval rapidly reduced the P4 release (by 50%). This reduction occurred 6 h earlier than those of infusions of PGF2 or Ang II alone. The simultaneous infusion of either 1) Ang II (10-6 M) with PGF2 (10-6 M), 2) ET-1 (10-7 M) with PGF2, or 3) Ang II + ET-1 with PGF2 (10-6 M) for 2 h also induced a rapid and pronounced (60%) decrease in P4 release. Perfusion with the Ang II antagonist blocked the P4-suppressing activity of Ang II alone or PGF2 + Ang II infusion. Ang II stimulated the release of ET-1 and oxytocin during infusion but inhibited them after infusion.
These results show that Ang II is released in the bovine midcycle CL in vitro, and this peptide, either alone or together with PGF2, can suppress the release of P4. As PGF2 directly stimulated Ang II release, Ang II may influence the critical period for starting the cascade of functional luteolysis in vivo and might lead to structural luteolysis with ET-1 as a major vasoconstrictor. The overall results suggest that Ang II may have an important role at luteolysis in the bovine CL.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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There is universal agreement that prostaglandin F2 (PGF2) is a physiological luteolysin in the cow. Injection of PGF2 has been shown to induce a dramatic decrease in luteal blood flow [9–11]. By using an in vivo microdialysis system (MDS) implanted in the bovine CL, we have previously shown that direct exposure of the microenvironment within the midcycle CL to PGF2 stimulated, but never inhibited, progesterone (P4) secretion [12]. This result suggests that PGF2 is most effective as a luteolytic factor when it reaches the CL through the blood flow. Endothelin-1 (ET-1) is a vasoconstrictive peptide that originates from endothelial cells [13]. Recently, we and others have shown that the production and release of ET-1 increased in the CL and ovarian venous plasma ipsilateral to the CL after PGF2 injection in the cow, and have proposed that ET-1 interacts with PGF2 as a local luteolytic factor [14–17]. It is likely that such vasoconstrictive peptides are responsible for an acute response to luteolytic PGF2 in both direct inhibition of P4 release and vasoconstriction of arterioles and, thereby, can start an acute drop in P4 release. Thus, the possibility arises that Ang II, also a local potent vasoconstrictor, may regulate the mechanisms involved in luteolysis in a fashion similar to that of ET-1. Indeed, Ang II has been shown to inhibit P4 production stimulated by LH in bovine luteal cells [18].
Therefore, in this study, we have examined and characterized possible local effects of Ang II and its interaction with PGF2 and ET-1 on P4 suppression as well as the release of peptides in bovine CL in vitro by using an MDS on a luteal explant as a model [19].
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The CL from Holstein cows were collected at a local slaughterhouse within 10–20 min of slaughter. The stage of the estrous cycle was carefully defined by macroscopic observation (size, color, consistency, connective tissue, thickness of endometrium, mucus, and absence/presence of elongated early embryo) of the ovaries (follicles and CL) and the uterus. CL were used that appeared to be from the mid-luteal phase on the basis of a CL diameter of 16–20 mm, a CL color of orange without visible connective tissue, a thin but healthy endometrium, and absence of a visible conceptus. They were washed several times with saline and transported at 38°C to the laboratory in saline containing 60 mg/L penicillin and 100 mg/L streptomycin.
MDS In Vitro
The MDS of the bovine CL in vitro has been previously described in detail [19]. In brief, each CL was cut to a 15-mm cube and divided into four pieces through the face of the apex. Three pieces were used for different experimental groups, and one piece was used for the control. Each experimental group and control group consisted of 5–9 luteal pieces derived from different CL. Each piece was separately penetrated by a 10-mm-long dialysis capillary (Fresenius SPS 900 Hollow Fibres; Fresenius AG, St. Wendel, Germany; cut-off Mr 1000) with each end glued to a 5-cm-long piece of silicone elastomer tubing (i.d. 0.3 mm). For perfusion, the four inlet tubes were connected to a multiple-line peristaltic pump, and the four outlet tubes were routed to a multiple-line fraction collector. The prepared luteal pieces were then placed in organ culture chambers (modified 2070 tube; Falcon, Franklin Lakes, NJ) that were maintained in a water bath at 38°C. The chambers were filled with 50 ml M199 (Sigma, St. Louis, MO) containing 10 mM NaHCO3, Earle's salts, 365 mg/L L-glutamine, 25 mM Hepes, 5 g/L BSA, 60 mg/L penicillin, 100 mg/L streptomycin, 2 mg/L amphotericin, and 56 mg/L ascorbic acid at pH 7.4. M199 was continuously renewed at a flow rate of 15 ml/h. The luteal pieces were perfused with Ringer's solution at a flow rate of 3.0 ml/h throughout the experiments. After a 3-h pre-perfusion, fractions of the perfusate were collected every 2 h (6 ml per fraction) up to 12–16 h (0 h corresponds to the end of the pre-perfusion). These conditions were selected because they had previously been shown to cause CL tissues to produce a constant release of P4, oxytocin (OT), ET-1, and Ang II. Collected samples were stored at -20°C until hormone determination.
In some of the experiments (for determining the response to different doses of Ang II, the effect of infusion with a mixed solution of substances, and the effect of activation of calcium channel and protein kinase C [PKC]), the substances were infused into the MDS between 2 and 4 h. When the experiment was intended to examine the effect of pre-stimulation with PGF2, PGF2 was first infused between 2 and 4 h, and then two following infusions with Ang II were applied between 4 and 6 h, and 8 and 10 h. For the antagonist experiment, stimulators such as PGF2, Ang II, and their combination (PGF2 + Ang II) were infused between 4 and 6h, while the Ang II antagonist was infused between 2 and 8 h. The substances infused into the MDS were PGF2, ionophore A23187, 12-o-tetradecanoylphorbol 13-acetate (TPA; Sigma), Ang II (Peptide Institute Inc., Osaka, Japan), [Sar1, Val5, Ala8]-Ang II (Ang II antagonist), and ET-1 (Peptide Institute Inc.). Each was diluted in Ringer's solution to obtain the required final concentrations.
The transfer capacity of the microdialysis membrane was determined by two in vitro experiments as described by Jarry et al. [20]. The transfer capacity was about 0.1% of the concentration infused as determined for OT, ET-1, and Ang II (Peptide Institute Inc.), and about 1% for P4 (Sigma).
Hormone Determination
P4, OT, ET-1, and Ang II concentrations were determined in the perfusate fractions from the MDS with second-antibody enzyme immunoassays (EIAs) that were based on the competitive assay using horseradish peroxidase-labeled P4 [21] or biotin-labeled peptides as tracers [16]. Concentrations of P4 were assayed directly for all fractions by using a polyclonal P4 antibody provided by Dr. K. Okuda, Okayama University. The standard curve of P4 ranged from 0.05 to 50 ng/ml, and the ED50 of the assay was 1.8 ng/ml. The intra- and interassay coefficients of variation (CVs) were on average 6.2% and 9.3%, respectively. Depending on the experimental design, the fractions were then pooled for the purpose of desalting and concentration of peptides. The volume was adjusted with Ringer's solution to 6 ml, BSA was added to these solutions to a final concentration of 1 mg/ml, and the solutions were adjusted to pH 2.5 with acetic acid. The samples were then applied to a Sep-pak C18 cartridge (Waters Millipore Corp., Milford, MA) according to the established method [16]. The samples were concentrated 25- to 30-fold as a result of the process. The average recoveries of synthetic OT, ET-1, and Ang II added to Ringer's solution were 73%, 62%, and 88%, respectively (n = 60 samples for each). The EIAs for OT and ET-1 were conducted as described previously by using a polyclonal OT antibody provided by Dr. T. Higuchi (Kochi University of Medicine, Japan), and a polyclonal ET-1 antibody provided by Dr. D. Schams (Technical University of Munich), as described previously [16]. The standard curve of OT ranged from 1.6 to 200 pg/ml, and the ED50 of the assay was 21 pg/ml. The intra- and interassay CVs of the OT assay were on average 6.2% and 8.6%, respectively. The standard curve of ET-1 ranged from 9.7 to 5000 pg/ml, and the ED50 of the assay was 450 pg/ml. The intra- and interassay CVs of the ET-1 assay were on average 8.7% and 12.6%, respectively. The cross-reactivities of ET-1 antibody with ET-1, ET-2, ET-3, and big endothelin were 100%, 50%, 22%, and 3%, respectively. The EIA for Ang II used rabbit anti-serum raised against human Ang II, provided by Dr. K. Wakabayashi (Gunma University, Japan). The EIA was otherwise identical to the EIAs for OT and ET-1. The standard curve of Ang II ranged from 2.4 to 10 000 pg/ml, and the ED50 of the assay was 110 pg/ml. The intra- and interassay coefficients of variation were on average 6.4% and 8.7%, respectively. The cross-reactivities of Ang II antibody with Ang I, Ang II, Ang III, and renin substrate were 10%, 100%, 50%, and 5%, respectively.
Statistical Analysis
All values (P4, OT, ET-1, and Ang II) were expressed as a percentage of the corresponding baseline, because of a large variation in the basal concentrations of each hormone (P4: CV = 27–77%, OT: CV = 69–158%, ET-1: CV = 19–64%, and Ang II: CV = 41–78%). This transformation enables an evaluation of relative changes of hormonal values between the different CL. The change in hormonal release was tested on the basis of individual time points throughout the experiment as compared with the baseline. Means were analyzed by ANOVA followed by Student's t-test. ANOVA with Duncan's new multiple-range test was used for the comparison among several treatment groups in the same time period. The absolute concentrations of each hormone during the first 2 h (baseline) of experiment are given in the results.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The release of hormones into the MDS from the midcycle CL was relatively constant over the experimental period. The baseline (100%) of each hormone was 5.1 ± 0.2 ng/ml for P4 (number of slices = 188), 6.3 ± 0.7 pg/ml for OT (n = 137), 2.1 ± 0.1 pg/ml for ET-1 (n = 125), and 3.9 ± 0.3 pg/ml for Ang II (n = 27). When the peptide extracts from several MDS perfusates from different CL were tested in the EIA for Ang II, they showed dose-dependent inhibition curves at dilutions from 1:1 to 1:64, which had good parallelism with the standard human Ang II. The Ang II release in the control slightly increased (by 40%) between 6 and 12 h. A 2-h perfusion of PGF2 (10-6 M) resulted in a significant (50–100%) increase in Ang II release from the luteal explants during the following experimental period (p < 0.05, Fig. 1).
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Dose-Dependent Effects of Ang II on P4 Release
Two infusions of Ang II (10-7 M, 10-6 M, and 10-5 M) between 2 and 4 h, and 6 and 8 h resulted in a dose- and time-dependent decrease of P4 release after the second infusion (p < 0.05). Ang II at 10-7 M and 10-6 M induced a significant decrease of P4 release after 8 h (p < 0.05), and the P4 release was suppressed by 41 ± 11% and 48 ± 5%, respectively, at 14–16 h. Ang II at 10-5 M induced a significant and rapid decrease of P4 release during the second substance infusion at 6–8 h (2 h earlier than occurred with the other doses; p < 0.05), and P4 release was significantly reduced (by 66 ± 3%) at 14–16 h (p < 0.05 vs. p values at 10-7 M and 10-6 M Ang II). For further experiments, a dose of 10-6 M was used for Ang II. This was based on 1) the expected concentration of Ang II in the intercellular fluid in the CL (~10-9 M, which corresponds to 10-6 M for the infusate of the MDS) and 2) the finding that a dose of 10-6 M suppressed P4 release.
Effects of Pre-Exposure with PGF2 on the Suppressing Activity of Ang II
A 2-h perfusion with PGF2 at 2–4 h (10-6 M) decreased the P4 release at 12–16 h (p < 0.05). Two 2-h perfusions of Ang II (10-6 M) at 4–6 h and 8–10 h similarly decreased the P4 release at 12–16 h (p < 0.05; Fig. 2). When the luteal explants were pre-perfused with PGF2 for 2 h at 2–4 h, two consecutive perfusions of Ang II at 4–6 h and 8–10 h rapidly decreased the P4 release from 6 h on; this decrease occurred 6 h earlier than in explants treated with PGF2 or Ang II alone (p < 0.05; Fig. 2). PGF2 significantly increased the release of both ET-1 and OT during the 2-h perfusion period (p < 0.05; Fig. 2). However, OT release decreased at 12–16 h (p < 0.05; Fig. 2). Ang II stimulated the release of ET-1 and OT during the infusion period, but it decreased the release of both peptides after the second infusion (p < 0.05; Fig. 2). In the group of CL pre-perfused first with PGF2 at 2–4 h followed by Ang II at 4–6 h and 8–10 h, PGF2 and the first infusion of Ang II stimulated ET-1 release, but after the second infusion of Ang II at 8–10 h, ET-1 release decreased (p < 0.05; Fig. 2). In this group, OT release was acutely stimulated by PGF2 infusion, and it was suppressed at 6–16 h (6 h earlier than the suppression appeared in the groups treated with PGF2 or Ang II alone; p < 0.05).
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Simultaneous Infusion of ET-1 and Ang II with PGF2
The simultaneous infusion of either 1) Ang II (10-6 M) with PGF2 (10-6 M), 2) ET-1 (10-7 M) with PGF2, or 3) Ang II + ET-1 with PGF2 (10-6 M) at 2–4 h induced a rapid and pronounced (60%) decrease in P4 release (p < 0.05; Fig. 3). However, PGF2 (10-6 M) alone at 2–4 h did not induce a significant decrease of P4 release until 12 h. PGF2 stimulated ET-1 release, while infusion of Ang II alone or Ang II with PGF2 stimulated ET-1 release but inhibited it at 10–12 h (p < 0.05; Fig. 3). Infusions of all substances at 2–4 h stimulated OT release during infusion, but inhibited it after infusion except for PGF2 alone (p < 0.05; Fig. 3).
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Effects of the Ang II Antagonist on the Suppressing Activity of Ang II
As shown in Figure 3, infusion of Ang II alone (10-6 M) at 2–4 h suppressed P4 release at 8–12 h (p < 0.05), whereas PGF2 alone (10-6 M) at 2–4 h did not decrease P4 release until 12 h. Infusion of Ang II with PGF2 at 4–6 h induced a rapid and pronounced inhibition of P4 release at 8–12 h (p < 0.05; Fig. 4). Perfusion with the Ang II antagonist (10-6 M) at 2–8 h blocked the P4-suppressing activity of Ang II alone and Ang II with PGF2 infusion at 4–6 h, while this antagonist treatment did not affect the pattern of P4 release stimulated by PGF2 (p < 0.05; Fig. 4). Infusion of Ang II with the antagonist and PGF2 + Ang II with the antagonist blocked the increase of ET-1 release during infusion at 4–6 h (p < 0.05). The Ang II antagonist itself stimulated OT release, and the infusion of PGF2 + Ang II with the antagonist rapidly decreased OT release (p < 0.05; Fig. 4).
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Effects of A23187 and TPA
The infusion of A23187 and TPA at 2–4 h stimulated P4 release from the luteal explants only during infusion. Both ET-1 and OT release were stimulated by A23187 during infusion, but they were suppressed at 8–12 h (p < 0.05; Fig. 5). Infusion of TPA at 2–4 h induced a decrease in ET-1 release at 6–12 h, while OT release was stimulated during TPA infusion at 2–4 h but was inhibited at 8–12 h after infusion (p < 0.05; Fig. 5). Ang II release in the control slightly increased (p < 0.05). Infusion of A23187 did not affect the release of Ang II. Contrary to the suppressing effects on ET-1 and OT release, infusion of TPA stimulated the Ang II release throughout the experimental period (p < 0.05; Fig. 5).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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or a concomitant infusion of Ang II with PGF2 inhibited the P4 release more rapidly than did an infusion of Ang II alone. This inhibition of P4 release is consistent with previous observations in which Ang II in the presence of LH inhibited P4 accumulation in cultured bovine luteal cells [18]. In the above study, Ang II significantly decreased LH-stimulated expression of the mRNA encoding cytochrome P450 side-chain cleavage (P450scc), and Ang II promoted the association of cholesterol with cytochrome P450scc in bovine luteal cells [18].
Ang II was detected in the MDS perfusate, and after stimulation with PGF2, Ang II release increased to 150–200% of the baseline throughout the experimental period. There are several lines of evidence that an RAS exists in the ovary and the CL. The levels of Ang II in rat ovarian tissue homogenates are much higher than levels found in an equivalent volume of plasma [2]. Renin mRNA is present in rat luteal cells [22], and renin-like enzyme [23, 24] and angiotensin-converting enzyme [5] have been identified in the CL of rats. Furthermore, active renin is also detected in the bovine CL [25]. In the present MDS study, the basal release of Ang II into the MDS perfusate was 3.9 ± 0.3 pg/ml. Thus, based on a transfer capacity of the microdialysis membrane of 0.1%, the expected local concentration of Ang II in the intercellular fluid within the CL is around 4 ng/ml. This range is at least 100-fold higher than the detectable plasma levels of Ang II in the cyclic cow (unpublished observation). All these results suggest that the bovine midcycle CL has a capacity to produce Ang II locally, although we cannot exclude the possibility that the stored Ang II was released during incubation of the luteal explants.
The P4 inhibitory effect of Ang II alone or combined with PGF2 was blocked by infusion of the Ang II receptor antagonist. This suggests that Ang II may affect P4 suppression via a receptor-mediated mechanism in the present model.
Cellular mechanisms involved in the actions of Ang II in luteal cells have been shown to be mediated in part by an increase in the intracellular concentration of intracellular free calcium ([Ca2+]i) in rats [3]. Accordingly, such an increase of [Ca2+]i may also play important roles in the actions of Ang II in the bovine CL. Namely, it is likely that PGF2 first activated this mechanism [26], and the following Ang II may have further hyperstimulated the increase of [Ca2+]i, resulting in a pronounced P4 inhibition. Likewise, a hypothesis could be drawn for the effect of ET-1 followed by PGF2 stimulation in the same MDS model [16]. Additionally, Ang II affected the release of ET-1 and OT. In bovine endothelial cells, Ang II enhanced the preproform of ET-1 mRNA [27, 28] and the release of immunoreactive ET-1 [29]. Ang II has been shown to stimulate ET-1 release through activation of PKC and mobilization of [Ca2+]i, which is caused by receptor-mediated phosphoinositide breakdown in endothelial cells [30]. Intracellular mechanisms of OT release from the bovine CL are also thought to be Ca2+- and PKC-dependent [31, 32].
Interestingly, the infusion of A23187 had no effect on the release of Ang II. This may reflect the unique process by which Ang II is produced by the local RAS. Namely, prorenin production in bovine thecal cells was found to be stimulated by LH and cAMP [33], and Ang I-converting enzyme in bovine endothelial cells was also found to be stimulated by cAMP [34]. These findings suggest that the production of RAS-related enzymes depends on cAMP activation. Moreover, TPA effectively stimulated the release of Ang II in the present MDS study. These data support the idea that PGF2 stimulates RAS through activation of the PKC system. It should be noted that Ang II is mainly produced on the cell surface through the conversion of Ang I in the intercellular fluid by angiotensin-converting enzyme present on the cell membrane. This is completely different from granule exocytosis, in which OT is released from large luteal cells [35]. It is also very different from ET-1 secretion based on a constitutive pathway starting at the transcriptional step of prepro-ET-1 followed by cleavage steps from big-ET-1 to ET-1 in endothelial cells [36].
On the basis of the present results, the following cascade-like local mechanisms of the early stage of luteolysis may be postulated. PGF2 directly and indirectly stimulates the release of luteal OT, ET-1, and Ang II, and they may interact with each other to stimulate a local release that is closely related to the increase of [Ca2+]i in the CL cells. Consequently, a hyperactivation of [Ca2+]i would occur in luteal cells in addition to the direct effect of PGF2, resulting in a rapid suppression of P4 release from those cells. At the same time, the vasoactive peptides may induce pronounced vasoconstriction of luteal arterioles, which would be followed by a severe depletion of blood flow into the CL.
In conclusion, Ang II is released in the bovine midcycle CL in vitro, and this peptide, either alone or together with PGF2, can suppress the release of P4. As PGF2 directly stimulated Ang II release, Ang II may influence the critical period for starting the cascade of functional luteolysis in vivo and might lead to structural luteolysis with ET-1 as a major vasoconstrictor. The overall results suggest that Ang II may have an important role in luteolysis in the bovine CL.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence. FAX: 81 155 49 5462; akiomiya{at}obihiro.ac.jp
Accepted: December 15, 1998.
Received: June 26, 1998.
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K. Hayashi, A. Miyamoto, B. Berisha, M. R. Kosmann, K. Okuda, and D. Schams Regulation of Angiotensin II Production and Angiotensin Receptors in Microvascular Endothelial Cells from Bovine Corpus Luteum Biol Reprod, January 1, 2000; 62(1): 162 - 167. [Abstract] [Full Text]
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T. J. Acosta, B. Berisha, T. Ozawa, K. Sato, D. Schams, and A. Miyamoto Evidence for a Local Endothelin-Angiotensin-Atrial Natriuretic Peptide Systemin Bovine Mature Follicles In Vitro: Effects on Steroid Hormones and Prostaglandin Secretion Biol Reprod, December 1, 1999; 61(6): 1419 - 1425. [Abstract] [Full Text]
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