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BOR - Papers in Press, published online ahead of print July 21, 2004.
Biol Reprod 2004, 10.1095/biolreprod.104.030270
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BIOLOGY OF REPRODUCTION 71, 1706–1711 (2004)
DOI: 10.1095/biolreprod.104.030270
© 2004 by the Society for the Study of Reproduction, Inc.

Ovary

Real-Time Relationships in Intraluteal Release among Prostaglandin F2{alpha}, Endothelin-1, and Angiotensin II During Spontaneous Luteolysis in the Cow1

Koumei Shirasuna3, Hitomi Asaoka3, Tomas J. Acosta3, Missaka P.B. Wijayagunawardane5, Masayuki Ohtani4, Misato Hayashi3, Motozumi Matsui3, and Akio Miyamoto2,3

Department of Agricultural and Life Science3 The Field Center of Animal Science & Agriculture,4 Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan Department of Animal Science,5 University of Peradeniya, Peradeniya 20400, Sri Lanka


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
It is well known that prostaglandin F2{alpha} (PGF2{alpha}) is a physiological luteolysine, and that its pulsatile release from the endometrium is a luteolytic signal in many species. There is now clear evidence that the vasoactive peptides endothelin-1 (ET-1) and angiotensin II (Ang II) interact with PGF2{alpha} in the luteolytic cascade during PGF2{alpha}-induced luteolysis in the cow. Thus, we investigated the local secretion of PGF2{alpha}, ET-1, and Ang II in the corpus luteum (CL) and their real-time relationships during spontaneous luteolysis in the cow. For this purpose, an in vivo microdialysis system (MDS) implanted in the CL was utilized to observe local secretion changes within the CL microenvironment. Each CL of cyclic Holstein cows (n = 6) was surgically implanted with MDS capillary membranes (18 lines/6 cows) on Day 15 (estrus = Day 0) of the estrous cycle. The concentrations of PGF2{alpha}, ET-1, Ang II, and progesterone (P) in the MDS samples were determined by enzyme immunoassays. The intraluteal PGF2{alpha} secretion slightly increased from 12 h after the onset of luteolysis (0 h) and drastically increased (by about 300%) from 24 h. Intraluteal ET-1 secretion increased from 12 h. Intraluteal Ang II secretion was elevated from 0 h and was maintained at high levels (about 180%) toward estrus. In each MDS lines (in the same microenvironment) within the regressing CL, the local releasing profiles of PGF2{alpha}, ET-1, and Ang II CL positively correlated with each other (P < 0.05) at high proportions in 18 MDS lines (PGF2{alpha} vs. ET-1, 44.4%; PGF2{alpha} vs. Ang II, 55.6%; ET-1 vs. Ang II, 38.9%). In contrast, there was no clear relationship among these substances released into different MDS lines implanted in the same CL (with different microenvironments). In conclusion, we propose that the increase of PGF2{alpha}, ET-1, and Ang II within the CL during luteolysis is a common phenomenon for both PGF2{alpha}-induced and spontaneous luteolysis. Moreover, this study illustrated the in vivo relationships in intraluteal release among PGF2{alpha}, ET-1, and Ang II during spontaneous luteolysis in the cow. The data suggest that these vasoactive substances may interact with each other in a local positive feedback manner to activate their secretion in the regressing CL, thus accelerating and completing luteolysis.

corpus luteum, corpus luteum function, ovary, progesterone


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
It is well known that prostaglandin F2{alpha} (PGF2{alpha}) is a physiological luteolysine, and that its pulsatile release from the endometrium is a luteolytic signal in many species [1]. Despite the endometrium, the corpus luteum (CL) was also recognized as a site of PGF2{alpha} production [2–5]. Several reports provided evidence that the CL expresses mRNA for cyclooxygenase-2 [6–8], prostaglandin F (PGF) synthase [9], as well as PGF receptors [10–12]. Moreover, in the bovine CL, intralueteal PGF2{alpha} secretion increases during PGF2{alpha}-induced luteolysis [13]. Thus, PGF2{alpha} secreted by the CL may play a role as an autonomous amplifier of uterine PGF2{alpha} during luteolysis. Although an injection of PGF2{alpha} drastically induces a decrease in progesterone (P) as well as CL volume during the midluteal phase in the cow [14], a direct exposure of the microenvironment within the midcycle CL to PGF2{alpha} using an in vivo microdialysis system (MDS) implanted in the bovine CL did not inhibit, but rather stimulated, P secretion [15]. These observations suggest that the transfer of PGF2{alpha} by blood flow to the CL is crucial for luteolysis in the cow.

We and others proposed that endothelin-1 (ET-1) [16– 18] and angiotensin II (Ang II) [19, 20], the predominant vasoconstrictive peptides, are the possible mediators of luteolytic action of PGF2{alpha} in the bovine CL. The peptides ET-1 [16–18] and Ang II [19, 20] are produced in the bovine CL, and receptors for endothelin (ETR-A and ETR-B) [7, 17] as well as angiotensin (AT1R and AT2R) [20, 21] are expressed in the bovine CL. Both ET-1 and Ang II have been shown to inhibit P secretion by bovine luteal cells [17, 18]. In ewes, following pretreatment with a subluteolytic dose of PGF2{alpha}, i.m. administration of ET-1 caused a rapid decline in plasma P and shortened the length of the estrous cycle [22]. Furthermore, our previous studies showed that a direct injection of ET-1 [23] or Ang II [24] into the CL after i.m. administration of a subluteolytic (1/ 4) dose of PGF2{alpha} analogue induced P suppression [23] or luteolysis followed by the estrus [24]. Additionally, PGF2{alpha} stimulates the release of ET-1 [7, 25] and Ang II [19, 26] both in vitro and in vivo. Thus, the findings described above strongly suggest that ET-1 and Ang II, together with PGF2{alpha}, induce a blood flow decrease [14, 27, 28] and P suppression [17, 18, 23, 24, 29] within the regressing CL induced by PGF2{alpha} injection.

Thus, it is hypothesized that ET-1 and Ang II interact with PGF2{alpha} in the luteolytic cascade and bear a critical role not only in PGF2{alpha}-induced luteolysis but also in spontaneous luteolysis in the cow. To determine whether the close relationship among these three substances is a common phenomenon during luteolysis, we aimed to investigate in detail the local secretion of PGF2{alpha}, ET-1 and Ang II in the CL and their relationships during spontaneous luteolysis in the cow. For this purpose, an in vivo microdialysis system (MDS) implanted in the CL was utilized to observe real-time, local secretion changes in the microenvironment within the CL.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals and Experimental Design

The experiment was carried out at the Field Centre of Animal Science and Agriculture, Obihiro University, and the experimental procedures complied with the Guide for Care and Use of Agriculture Animals of Obihiro University. Six multiparous, nonlactating Holstein cows were used for this study. They had at least two estrous cycles of normal length (21– 22 days) before being used. Luteolysis was induced by i.m. injection of 500 µg of a PG2{alpha} analogue (cloprostenol, Estrumate; Takeda Co., Osaka, Japan), and 100 µg of GNRH (Conceral; Takeda) was injected i.m. 60 h after the PGF2{alpha} injection to ensure ovulation. The day of estrus was designated as Day 0. The MDS membranes were surgically implanted into the CL on Day 15 of the estrous cycle. After the surgery, cows were moved to individual stanchions, and were fed hay and water ad libitum. Sample collection was started 24 h after surgery and continued until the next estrus. After the experimental period, the MDS was surgically removed and the cow was ovariectomized. The occurrence of luteolysis was confirmed by macroscopic observation of dissected CL [30]. The time schedule of the present study is shown in Figure 1.



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  		FIG. 1. Time schedule of MDS treatment in vivo

Surgical Implantation of the MDS into the CL and Venous Catheterization

The MDS was surgically implanted into the CL on Day 15 of the estrous cycle via lateral laparotomy under epidural anesthesia as described previously [25]. Before surgery, ovaries were monitored by transrectal ultrasonography to determine that the CL was normal and had no cystic cavity. Basically, two to five dialysis capillary membranes (cutoff = 1000 kDa, 0.2 mm diameter, 10 mm long; Fresenius SPS 900 Hollow Fibers; Fresenius AG, St. Wendel, Germany) were implanted into the CL. Both ends of the capillary membranes were glued to 25-cm-long pieces of silicone elastomer tubing (inner diameter 0.3 mm) and connected to the MDS. The tubing was fixed on the surface of the CL by Histoacryl blau (B. Braun-Dexon GmbH, Spangenberg, Germany), and the dialysis pieces with silicone tubing were connected to Teflon tubing that led to the outside of the abdomen. The exteriorized bundle of afferent and efferent Teflon tubing was fixed on the back of the cow. One end of the MDS was connected to a multiple-line peristaltic pump, and the other was connected to a multiple-line fraction collector. The MDS was continuously perfused with Ringer solution at a flow rate of 2.5 ml/h throughout the experiment, and fractions of perfusate were collected at 4-h intervals. Sample collection started 24 h after surgery, and all MDS samples were immediately frozen at –30°C after collection until further analysis.

Hormone Determination

The concentrations of P, PGF2{alpha}, ET-1, and Ang II in perfusate fractions of the MDS were determined in duplicate by second antibody enzyme immunoassays (EIAs) after extraction using 96-well enzyme-linked immunosorbent assay plates (NUNC-Immuno Plate; NUNC Brand Products, Denmark).

The P concentrations in perfusate fractions of the MDS were assayed directly [31]. The standard curve ranged from 0.05 to 50 ng/ml, and the ED50 of the assay was 2.4 ng/ml. The intra- and interassay coefficients of variation (CVs) averaged 6.2% and 9.3%, respectively.

To extract PGF2{alpha}, the MDS perfusates (6 ml) were adjusted to pH 3.5 using HCl and extracted using diethyl ether as described previously [32]. The residue was dissolved in 200 µl of assay buffer (40 mM PBS, 0.1% BSA, pH 7.2). Samples were thus concentrated 30-fold for the MDS perfusate. To estimate the recovery rate in the MDS perfusate, PGF2{alpha} was added to the Ringer solution, and the obtained values were 65%. The EIAs for PGF2{alpha} [33] were described previously. The standard curve for PGF2{alpha} ranged from 9.5 to 9500 pg/ml, and the ED50 of the assay was 145 pg/ ml. The intra- and interassay CVs were 7.7% and 9.7%, respectively.

To extract peptides for the MDS perfusates, the remaining Ringer solution after diethyl ether extraction was used for peptide extractions. Bovine serum albumin (fraction V; Sigma Chemical Co., St. Louis, MO) was added to the MDS samples to a final concentration of 1 mg/ml, and the pH was adjusted to 2.5 with acetic acid. All samples were then applied to a SepPak C18 Cartridge (Waters, Millford, MA) as described previously [18]. The residue was evaporated and then dissolved in 250 µl of assay buffer (42 mM Na2HPO4, 8 mM KH2PO4, 20 mM NaCl, 4.8 mM EDTA, 0.05% BSA, pH 7.5) for peptide EIAs. Thus, the samples were concentrated 24-fold for the MDS perfusate as a result of this process that enabled us to determine peptide concentrations in EIA within the range of a standard curve. The recovery rates of ET-1 and Ang II that had been added to Ringer solution were 61% and 82%, respectively. The EIAs for ET-1 [18] and Ang II [19] were described previously. The standard curve for ET-1 ranged from 0.5 to 500 pg/ml, and the ED50 of the assay was 25 pg/ ml. The intra- and interassay CVs were 8.7% and 12.6%, respectively. The standard curve for Ang II ranged from 5 to 5000 pg/ml, and the ED50 of the assay was 125 pg/ml. The intra- and interassay CVs were 6.4% and 8.7%, respectively. The data for PGF2{alpha}, ET-1, and Ang II were corrected for extraction losses.

Statistical Analysis

A large variation was observed in the absolute amount of substances released into each of the microdialysis capillary membranes implanted in different cows. Thus, for analysis of changes in concentrations of substances in the MDS fractions, the mean concentrations of the first six fractions (24 h) were used to calculate an individual proportion of baseline. All concentrations in the fractions collected were then expressed as a proportion of this individual baseline. This treatment enables an evaluation of the relative changes of substance values between the CL of different animals. The time point when P concentrations in MDS fractions started to decrease was considered as 0 h for the data analysis. For statistical analysis, the experimental period was divided into 12 stages, and each represents the assortment of the data from a 12-h period (3 fractions). The data on substances released into microdialysis capillary membranes during the different stages were analyzed using a Student t-test followed by an F-test. Differences were considered significant at a probability less than 5% (P < 0.05). Pulsatile releases of PGF2{alpha}, ET-1, and Ang II in the MDS during spontaneous luteolysis were examined. The occurrence of peaks was identified when the proportional changes of PGF2{alpha}, ET-1, and Ang II increased from basal values at least over 3-fold of the intraassay CV of EIAs. The relationship among peaks of PGF2{alpha}, ET-1, and Ang II in the MDS were analyzed using a chi-square test of independence for contingency. P < 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The estrous signs were observed in all cows between Days 21–23 from the last estrus, and CLs implanted with MDS were collected by ovariectomy after the estrus. The regression of CLs was confirmed by macroscopic observation.

Intralueteal Changes in P, PGF2{alpha}, ET-1, and Ang II Concentrations During Spontaneous Luteolysis

The basal release (100%) of P, PGF2{alpha}, ET-1, and Ang II into MDS fractions implanted in the CL was 1.57 ± 0.27 ng/ml, 18.52 ± 1.52 pg/ml, 0.28 ± 0.03 pg/ml, and 0.31 ± 0.02 pg/ml (mean ± SEM), respectively. These basal releases of P, PGF2{alpha}, ET-1, and Ang II was constant before the onset of luteolysis. The intralueteal P secretion started to decrease on Day 17–18 (the onset of luteolysis = 0 h), and declined further to about 20% of baseline at the end of the experiment (Fig. 2A). The intralueteal PGF2{alpha} secretion increased slightly from 12 h after the onset of luteolysis, drastically increased from 24 h to about 300%, and was maintained at high levels toward the estrus (Fig. 2B). The intralueteal ET-1 secretion increased at 12–36, 48–72, and 84–96 h after the onset of luteolysis, and was maintained at high levels (about 140%) toward estrus (Fig. 2C). Intralueteal Ang II secretion started to increase immediately after the onset of luteolysis, and was maintained at high levels (about 180%) during the experimental period (Fig. 2D).



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  		FIG. 2. Local release of P (A), PGF2{alpha} (B), ET-1 (C), and Ang II (D) into MDS (bars; 18 lines from 6 cows) during spontaneous luteolysis cows (mean ± SEM). The MDS data are expressed as a percentage of basal release (baseline) for the first 24 h (100% = 1.54 ± 0.27 ng/ml for P, 18.52 ± 1.52 pg/ml for PGF2{alpha}, 0.31 ± 0.02 pg/ml for ET-1, and 0.28 ± 0.03 pg/ml for Ang II). Different superscripts denote statistically different values (P < 0.05)

Relationship in Local Release among PGF2{alpha}, ET-1, and Ang II

A relationship of the peaks among intralueteal PGF2{alpha}, ET-1, and Ang II is shown in Table 1. In each MDS line (the same microenvironment) within the regressing CL, the local releasing profiles of PGF2{alpha}, ET-1, and Ang II CL positively correlated with each other (P < 0.05) at high proportions from the 18 MDS lines implanted in the 6 CLs (PGF2{alpha} vs. ET-1, 44.4%; PGF2{alpha} vs. Ang II, 55.6%; ET-1 vs. Ang II, 38.9%). An example of intralueteal secretion among PGF2{alpha}, ET-1, and Ang II into a single MDS line (the same microenvironment) is shown in Figure 3. On the other hand, there was no clear relationship among the same substances (PGF2{alpha}, ET-1, and Ang II) released into different MDS lines implanted in the same CL (different microenvironments; Fig. 4).


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  		TABLE 1. Relationship of secretion profiles among intraluteal PGF2{alpha}, ET-1, and Ang II in vivo (n = 18 lines/6 cows)



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  		FIG. 3. Relationship of the peaks among intraluteal PGF2{alpha}, ET-1, and Ang II into a single MDS line (the same microenvironment) in one cow (#142). The inverted black triangle indicates the coincident peaks, the gray triangle indicates intraluteal PGF2{alpha}, the white square indicates intraluteal ET-1, and the black circle indicates intraluteal Ang II



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  		FIG. 4. Relationship among intraluteal PGF2{alpha} (a), ET-1 (b), and Ang II (c) into different MDS lines implanted in the same corpus luteum (different microenvironments) in one cow (#151). The same symbol in each graph indicates the same MDS line


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of the present study demonstrate that the local release of ET-1 and Ang II as well as PGF2{alpha} increased after the onset of spontaneous luteolysis in the cow. The in vivo MDS used in the present study enabled us to precisely evaluate a real-time relationship of local factor secretions within the microenvironment of intact CLs in which the cell-to-cell integrity and communication could be maintained.

It has been shown that the vasoactive peptides ET-1 and Ang II may play an essential role during luteolysis in the cow [7, 17–19, 24, 25]. In the present study, intralueteal release of ET-1 and Ang II increased together with intralueteal PGF2{alpha} after the onset of spontaneous luteolysis. Previously, we demonstrated the real-time changes of intralueteal ET-1 [25] and Ang II [26] release within the regressing CL during PGF2{alpha}-induced luteolysis by using an identical in vivo MDS implanted in the mid-CL in the cow. In those studies, the intralueteal release of ET-1 and Ang II increased immediately after i.m. PGF2{alpha} administration [25, 26]. Moreover, intralueteal release of PGF2{alpha} was acutely stimulated by i.m. PGF2{alpha} administration, but it chronically increased from 12 h onward [13]. Therefore, these findings indicate that the increase in local secretion of these vasoactive substances within the CL is the common mechanism during luteolysis. Several reports revealed an interaction among PGF2{alpha}, ET-1, and Ang II in vivo [21, 25, 26, 34] and in vitro [17, 19] in the cow. It has been shown that PGF2{alpha} stimulates the release of ET-1 [7, 25] and Ang II [19, 26] in the CL in vivo and in vitro in the cow. Also, PGF2{alpha} has been shown to stimulate mRNA expression for ET-1 [7, 35] and peptide concentration for ET-1 and Ang II [21] in the cow. On the other hand, Ang II stimulates the release of PGF2{alpha} and ET-1 [19, 36] as well as the amount of mRNA encoding prepro ET-1 in bovine endothelial cells [37]. In addition, it was reported that ET-1 enhances biosynthesis and release of PGF2{alpha} from human luteal cells [38]. In the present in vivo study, we observed that intralueteal release of PGF2{alpha}, ET-1, and Ang II in each MDS line (in the same microenvironment) positively correlated with each other at high proportions during spontaneous luteolysis in the cow. Thus, during spontaneous luteolysis, PGF2{alpha}, ET-1, and Ang II may establish a local positive feedback loop within the microenvironment in the regressing CL (Fig. 5).



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  		FIG 5. A possible model for local positive feedback among intraluteal PGF2{alpha}, ET-1,and Ang II during spontaneous luteolysis

We and others have demonstrated that ET-1 and Ang II inhibited P release in the CL of bovine [17–19] and human [29] in vitro. In addition, an intralueteal injection of ET-1 [23] or Ang II [24] after i.m. administration of a subluteolytic dose of PGF2{alpha} analog induced a decrease in P release. Importantly, a direct exposure, but not via blood circulation, of the microenvironment within bovine mid-CL to PGF2{alpha} alone by using in vivo and in vitro MDS stimulated P release, but did not inhibit it [15, 39]. However, a concomitant infusion of ET-1 or Ang II with PGF2{alpha} effectively inhibited P release [19]. It is also known that the blood flow into the CL decreases during luteolysis [14, 27, 28]. Thus, it is likely that a local positive feedback system among PGF2{alpha}, ET-1, and Ang II in the CL after onset of luteolysis may ensure the decrease in P secretion, and at the same time induce a chronic, severe vasoconstriction to interrupt the luteal blood supply.

The bovine CL contains relatively large amounts of arachidonic acid that are comparable to those in endometrial cells [40], and the functional arachidonic acid-prostaglandin metabolic pathway is identified in the bovine CL [2, 3]. The coadministration of indomethacin, a potent prostaglandin synthase inhibitor, and PGF2{alpha} to both pigs and sheep prevented the increase in luteal PGF2{alpha}, but P levels fell despite this blockade. In addition, a recent study in sheep reported that intralueteal implants of indomethacin did not prevent the decline in plasma P levels at the expected time of spontaneous luteolysis. However, while functional luteolysis was apparent in these animals, structural luteolysis did not occur at the end of the cycle, and luteal weights were maintained [41]. Furthermore, the systemic administration of prostaglandin synthesis inhibitors delayed the structural luteolysis in rats [42]. In the present study, the intralueteal PGF2{alpha} secretion was drastically increased from 24 h after the onset of luteolysis. These data demonstrated that intralueteal production of PGF2{alpha} is required not for functional luteolysis, but for structural luteolysis.

There was no relationship in the secretion profiles of PGF2{alpha}, ET-1, or Ang II released into different MDS lines within the same CL. This suggests that the different secretion pattern occurs in different microenvironments within the CL. Vascular endothelial cells that produce and release ET-1 and Ang II represent more than 50% of the total number of cells in the CL [43, 44]. Additionally, it was shown that the functional distribution of the cells is heterogeneous within the CL [45]. Therefore, the regional blood flow and the type of cell populations that contact the implanted MDS capillary membrane may depend on the area of the CL. Thus, the pattern of substance release into MDS may be different between the lines implanted at different sites. These findings strongly support the concept that CL regresses heterogeneously; therefore, the destruction of the CL tissue occurs with a slight time lag in different microenvironments.

We previously showed that a luteolytic injection of PGF2{alpha} induces an acute increase in the local blood flow that runs the periphery of the CL [14]. Nitric oxide (NO) is known to serve as a strong vasorelaxant that increases local blood flow, and has emerged as an important mediator of luteolysis in the cow, because the inhibitor of NO synthase prevents the occurrence of spontaneous and PGF2{alpha}-induced luteolysis in this species [46, 47]. Also, NO may function to antagonize the action of ET-1, hence, a balance between NO and ET-1 or Ang II may occur within the CL to regulate luteal blood flow. These findings suggest that a luteolytic injection of PGF2{alpha} may induce NO release in arterioles that surround the periphery of the CL, and that the increased luteal blood flow triggers a luteolytic cascade in the cow.

In conclusion, this study provides the first in vivo evidence for relationships in intralueteal release among PGF2{alpha}, ET-1, and Ang II after the onset of spontaneous luteolysis in the cow. The data suggest that these vasoactive substances may interact with each other in a local positive feedback manner to activate their secretion in the regressing CL, thus accelerating and completing luteolysis.


   ACKNOWLEDGMENTS
 
We thank Dr. K. Okuda, Okayama University, Japan, for P antiserum; Dr. S. Ito, Kansai University of Medicine, Japan, for PG antiserum; Dr. K. Wakabayashi, Gunma University, Japan, for Ang II antiserum; Dr. D. Schams, Technical University of Munich, Germany, for ET antiserum; and Fresenius AG, St. Wendel, Germany, for microdialysis capillary membranes.


   FOOTNOTES
 
1 This study was supported by the Grant-in-Aid for Scientific Research of the Japan Society for the Promotion of Science (JSPS) and the 21st Century COE Program (A-1), Ministry of Education, Culture, Science and Technology of Japan. T.J.A. and M.P.B.W. are postdoctoral fellows supported by JSPS. M.M is supported by the COE Program. Back

2 Correspondence. FAX: 81 155 49 5593; akiomiya{at}obihiro.ac.jp Back

Received: 29 March 2004.

First decision: 4 May 2004.

Accepted: 9 July 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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