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Regular Article |
, and Steroid Hormones from Bovine Mature Follicles In Vivo1
a Departments of Theriogenology and
b Animal Science, and
c University Farm, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan
d Institute of Physiology, Technical University of Munich, 80350 Freising-Weihenstephan, Germany
e Departamento de Fisiologia, Facultad de Ciencias Veterinarias Universidad Nacional de Asuncion, San Lorenzo, Paraguay
ABSTRACT
We previously proposed that an endothelin-angiotensin-atrial natriuretic peptide system may contribute to inducing ovulation of mature bovine follicles by modulating follicular secretion of steroids and prostaglandins (PGs). Thus, this study aimed to determine the real-time changes in the local release of angiotensin II (Ang II), endothelin (ET), atrial natriuretic peptide (ANP), PGF2
, and steroid hormones from bovine mature follicles during the periovulatory period in vivo. Seven cows were treated for superovulation using FSH and PGF2 injections. Two dialysis capillary membranes per follicle were surgically implanted into the theca layer of mature follicles and connected to a microdialysis system (MDS). Fractions of the perfusate were collected from Day -1 (Day 0 = LH surge) to Day 3. Five out of seven treated cows were normally ovulated, and the newly formed corpora lutea were observed at the end of the experiment. In these five ovulated cows, the release of estradiol, androstenedione, and progesterone in the theca layer increased (P < 0.05) synchronously with the LH surge. Acute increases in PGF2 and Ang II concentrations in the ovarian venous plasma (OVP) were observed at 24–48 h after the peak of the LH surge, when multiple ovulations were expected to occur. The follicular Ang II release was low during the pre-LH surge period and rose (P < 0.05) at the beginning of the increase in the LH surge. On the other hand, ET-1 release dropped (P < 0.05) when plasma LH started to increase. However, no clear changes in ANP concentration in the MDS perfusate and plasma were observed. The above local changes in Ang II, PGF2, as well as steroid hormones were not observed in cows (n = 2) that did not show an LH surge and ovulation. The present results demonstrate for the first time the local release of Ang II, ET-1, and ANP from the bovine mature follicle in real-time in vivo and show that Ang II and PGF2 concentrations in the OVP acutely increase around the time of ovulation. The overall results support the concept of a local functional ET-Ang-ANP system in the bovine mature follicle that may be involved in the ovulatory process.
follicle, granulosa cells, ovary, ovulation, theca cells
INTRODUCTION
Ovulation occurs as a result of a dynamic interaction among the LH surge and local follicular factors including steroids, prostaglandins (PGs), and peptides in a time-dependent manner. The LH surge triggers a biochemical cascade that leads to the rupture of the Graafian follicle, resulting in the expulsion of the oocyte and consequent development of the corpus luteum (CL).
The crucial roles of PGs in ovulation have been demonstrated by experiments in which inhibitors of PG biosynthesis effectively inhibited ovulation in the rat [1], rabbit [2, 3], and cow [4]. The levels of PGE2 and PGF2 increased more than 100-fold at 25 h after the endogenous LH surge in bovine preovulatory follicular fluid [4]. The local increase in the PG concentration induces vasodilatation in the follicular vessels, augments vascular permeability, and stimulates the collagen breakdown that is necessary for follicular rupture [5].
Several lines of evidence indicate that angiotensin II (Ang II), endothelin-1 (ET-1), and atrial natriuretic peptide (ANP) regulate reproductive phenomena such as ovulation, oocyte maturation, and CL function [6–12]. Moreover, Ang II, ET-1, and ANP have been shown to modify the synthesis and secretion of hormones produced in ovarian follicular cells in an autocrine and/or paracrine manner [13–17]. The high concentrations of these vasoactive peptides in the different ovarian compartments [18, 19], the presence of their specific receptors [15, 20–22], and the cyclic variation in their ovarian activities in the course of the estrous cycle [16, 23–25] demonstrated that these vasoactive peptides play important roles in ovarian physiology. We recently found that a local infusion of Ang II, ET-1, or ANP using a microdialysis system (MDS) implanted in the theca layer of bovine mature follicles enhanced the secretion of PGF2 in vitro [18]. The same study further demonstrated the presence of a functional Ang-ET-ANP system in the bovine preovulatory follicles. However, there is no in vivo information available so far on the local secretion of vasoactive peptides, PGF2, and steroid hormones from bovine follicles during the periovulatory period.
Therefore, the objective of this study was to determine in detail the real-time changes in the local release of Ang II, ET-1, ANP, PGF2, and steroid hormones from the bovine mature follicles along with the changes in ovarian venous plasma (OVP) as well as in jugular venous plasma (JVP) in vivo.
MATERIALS AND METHODS
Animals
The animal experiment was carried out at the Institute of Physiology, TU Munich-Weihenstephan, Germany. Seven multiparous, nonlactating Simental cows were used for this study. The cows were induced to have multiple ovulation by a half-dose (9 mg) of FSH (Ovagen; Immuno-chemical products Ltd., Auckland, New Zealand) in total. A schematic time schedule of the superovulatory treatment and the MDS is shown in Figure 1. Two intramuscular injections were given daily at 0700 h and 1800 h during 4 days, starting among the Day 8 and 11 of the estrous cycle (the day of the estrus was designated as Day 0). On the third day of the FSH treatment, at 1400 h, a luteolytic dose of 500 µg of cloprostenol (estrumate; Mallinckrodt GmbH Burgwedel, Germany), a PGF2 analogue, was intramuscularly injected. At 18–22 h after cloprostenol injection, a laparotomy was performed as described previously [24] to surgically implant the MDS capillary membranes into the follicular wall of mature follicles and to canulate the ovarian vein ipsilateral to the implanted MDS. A jugular venous catheter was also implanted. Before surgery, the ovaries were monitored by transrectal ultrasonography to determine the size and number of the developing follicles and the side of the regressing CL. After surgery, the cows were moved to individual stanchions, where they were fed daily with corn silage and hay with permanent free access to water. At the end of the experiment (Day 3 after the LH surge), the cows were ovariectomized and the ovaries were visually inspected for the presence of CL and the location of the MDS within the CL, most of the tubes were surrounded by luteal tissue.
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Implantation of the MDS Capillaries into the Follicular Wall
The MDS for bovine mature follicles was based on the method developed for porcine follicles in vivo [26], and the same system was applied previously to the bovine CL in vivo [24] with some modifications. The MDS capillary membranes were implanted in the theca layer of follicles in the ovary contralateral to the regressing CL. Only follicles that were at least 13 mm in diameter were implanted. The implant was done via a lateral laparotomy under epidural anesthesia as described previously [14, 24]. Basically, two dialysis capillary membranes (Fresenius SPS 900 Hollow Fibers, cutoff = 1000 kDa, 0.2 mm diameter, 5 mm long; Fresenius AG, St. Wendel, Germany) were implanted into the lateral side of the follicular wall using a 25-gauge hypodermic needle. Both ends of the capillary were glued to a 25-cm-long piece of silicone elastomer tubing (inner diameter 0.3 mm) and connected to the MDS. The tubing was fixed on the surface of the follicular wall 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 experiments, and the fractions of the perfusates were collected at intervals of 4 h starting at Day -1 for the next 5 days. During this period, most of the implanted follicles ovulated and developed to functional CL, thus allowing the determination of the local secretory changes during the process of ovulation and new CL formation.
At surgery an 18-gauge catheter (Medicut Catheter Kit; Argyle Co., Japan Sherwood, Tokyo, Japan) was inserted into the ovarian vein ipsilateral to the implanted MDS and sutured. The JVP and OVP for determination of peptides, PGF2, and steroid hormones were collected from the start of the experiment at 2-h intervals until 64 h, and then at 4-h intervals into sterile 10-ml tubes containing 200 µl of a stabilizer solution (0.3 M EDTA, 1% acid acetyl salicylic, pH 7.4). All tubes were immediately chilled in ice water for 10 min, centrifuged at 2000 x g for 10 min at 4°C, and the obtained plasma was frozen at -30°C until further analysis.
Steroid and PGF2 Extraction
The OVP samples for steroids (300 µl) were extracted by diethyl ether. The plasma samples (OVP and JVP, 2 ml) and the MDS perfusates (8 ml) were adjusted to pH 3.5 using HCl and extracted using diethyl ether as described previously [18]. The residue was dissolved in 200 µl assay buffer (40 mM PBS, 0.1% BSA, pH 7.2) for plasma samples and in 300 µl for MDS perfusates, thus concentrated 10-fold and 26.7-fold, respectively. The recovery rates of steroids and PGF2 were validated earlier to 75% for estradiol-17ß (E), 81% for androstenedione (A), 88% for progesterone (P), and 64% for PGF2 in our laboratory. To estimate the recovery rate in the MDS perfusate, E, A, P, and PGF2 were added to Ringer solution (5, 30, 100, and 10 pg/ml, respectively), and the obtained values were 77%, 84%, 90%, and 65%, respectively.
Peptide Extraction
The plasma samples (6 ml) were diluted with 5 ml of distilled water, and the pH was adjusted to 2.5. For the MDS perfusates, the remaining Ringer solution after diethyl ether extraction was used for peptide extractions. Bovine serum albumin (Sigma Chemical Co., St. Louis, MO; fraction V) 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 Sep-Pak C18 Cartridge (Waters, Millford, MA) as described previously [27]. The residue was evaporated and then dissolved in 250 ml assay buffer (42 mM Na2HPO4, 8 mM KH2PO4, 20 mM NaCl, 4.8 mM EDTA, 0.05% BSA, pH 7.5) for peptide enzyme immunoassays (EIAs). Thus, the samples were concentrated 24-fold for plasma and 32-fold for the MDS perfusate as a result of this process that enabled us to determine peptide concentrations in EIA within the range of standard curve. The recovery rates of Ang II (100 pg/ml), ET-1 (10 pg/ml), and ANP (100 pg/ml) that had been added to the plasma were 89%, 57%, and 76%, respectively. The recovery rates of Ang II (10 pg/ml), ET-1 (5 pg/ml), and ANP (20 pg/ml) that had been added to the Ringer solution were 92%, 63%, and 67%, respectively.
Hormone Determinations
The concentrations of Ang II, ET-1, ANP, PGF2, and steroids in the plasma and perfusate fractions of the MDS were determined in duplicate by second antibody EIA after extraction using 96-well ELISA plates (Corning Glass Works, Corning, NY) as described earlier [18, 27].
The EIA for Ang II was performed as described previously [12]. The standard curve ranged from 2.5 to 2500 pg/ml and the ED50 of the assay was 125 pg/ml. The intra- and interassay coefficients of variation (CVs) were 5.5 and 8.3%, respectively. The EIAs for ET-1 were performed as described previously [18]. The standard curve ranged from 10 to 500 pg/ml and the ED50 of the assay was 60 pg/ml. The intra- and interassay CVs were 7.5 and 12.5%, respectively. The EIA for ANP was performed as described elsewhere [18]. The standard curve ranged from 30 to 30 000 pg/ml, and the ED50 of the assay was 850 pg/ml. The intra- and interassay CVs were 6.5 and 10.4% respectively.
The EIA for PGF2 was also described [28]. The standard curve for PGF2 ranged from 7 to 7000 pg/ml, and the ED50 of the assay was 245 pg/ml. The intra- and interassay CVs were 7.7 and 13.0%, respectively.
The EIA for P was done as previously described [29]. The standard curve ranged from 0.05 to 25 ng/ml, and the ED50 of the assay was 2.4 ng/ml. The intra- and interassay CVs were 4.7 and 6.5%, respectively. The EIA for E was carried out as described previously [28]. The standard curve ranged from 2 to 2000 pg/ml, and the ED50 of the assay was 105 pg/ml. The intra- and interassay CVs were 6.5 and 7.6%, respectively. The EIA for A was described elsewhere [14]. The standard curve ranged from 2 to 1000 pg/ml, and the ED50 of the assay was 110 pg/ml. The intra- and interassay CVs were 6.5 and 7.3%, respectively.
The plasma LH concentration was determined directly in duplicate 20-µl JVP samples using a sensitive EIA for LH determination in bovine plasma based on the streptavidin-biotin technique as previously described [30]. The standard curve for LH ranged from 0.2 to 200 ng/ml, and the ED50 of the assay was 10.5 ng/ml. The intra- and interassay CVs were 8.5 and 13.5%, respectively.
Statistical Analysis
Due to the individual variation in the interval from the cloprostenol injection to the endogenous LH surge among animals, the peak of the LH surge in the JVP was considered as 0 h for the analysis of changes in the vasoactive peptides, PGF2 and steroid concentrations during the experimental period. The mean concentrations of Ang II, ET-1, ANP, and PGF2 in the MDS fractions, OVP and JVP samples collected at different time periods related to the peak of the LH surge were compared on the basis of each 24-h period. To compare the values of concentrations between OVP and JVP, the mean values of each 24-h period were analyzed by ANOVA followed by Student's t-test. The mean absolute concentrations of peptides, PGF2, and steroids were analyzed on the basis of the above 24-h period throughout the experiment by ANOVA followed by Fisher's protected least significant difference test. Differences were considered significant at a probability <5% (P < 0.05).
RESULTS
Ovarian Response to Superovulation
The number of follicles with diameters >13 mm per ovary at the time of surgery was 6 ± 2.2 (mean ± SEM). Of the seven cows used in this study, five cows showed an endogenous LH surge between 36 and 64 h (54.7 ± 5.0 h) after a luteolytic injection of cloprostenol. The basal JVP concentration of LH was 2 ± 1.5 ng/ml, and the peak values of LH surge ranged from 15 to 54.5 ng/ml (26.4 ± 6.6 ng/ml). In the remaining two cows, the JVP concentrations of LH remained low (<4 ng/ml) throughout the experimental period and ovulation did not occur, which was confirmed by visual inspection of the ovaries at the end of the experiment after ovariectomy. At the expected ovulation time (follicular rupture) 22% of the MDS lines stopped, thus only the perfusates collected until the end of the experiment were analyzed (18 lines from five cows with LH surge and 10 lines from two cows without LH surge).
Changing Profiles of Steroid Hormones During the Periovulatory Period
The changes of steroid hormone concentrations in the MDS perfusates and OVP in five cows with an LH surge and two cows without an LH surge are shown in Figure 2. The follicular release of E and A into the MDS perfusates increased synchronously with the endogenous LH surge (Fig. 2a). The increase in the follicular releases of E and A were coincident with their increases in concentration in the OVP. The E concentration was high during the pre-LH surge period, reached a peak during the LH surge, and then dropped to lower levels 12 h thereafter (P < 0.01). Follicular release of P temporarily increased (P < 0.05) when the plasma LH concentration started to rise and decreased during the peak of LH surge. Both plasma and follicular P levels started to increase (P < 0.05) 24 h after the LH surge, indicating the initiation of luteinization in granulosa and theca cells. The above clear changes seen in the ovulated cows were not observed in the unovulated two cows (Fig. 2b).
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Changing Profiles of PGF2 During the Periovulatory Period
Changes of PGF2 concentrations in five cows with an LH surge are shown in Figure 3a, and the corresponding changes in two cows without an LH surge are shown in Figure 3b. The concentrations are given for the MDS fractions (bars), OVP (closed circles), and JVP (open circles). Acute increases in PGF2 concentration (P < 0.001) in OVP as well as in the MDS perfusates were observed between 24 and 48 h after the LH surge, when multiple ovulations were expected to occur (Fig. 3a and Table 1). This increase was not observed in the two cows without an LH surge (Fig. 3b). The PGF2 concentration was higher in the OVP than in the JVP (P < 0.001) before the LH surge and dropped as the LH surge approached, or the equivalent time period in the two cows without an LH surge. These changes in the OVP and the MDS fractions were not detected in the JVP, where the concentrations of PGF2 remained low and stable (Table 1).
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Follicular Release and Plasma Concentrations of Vasoactive Peptides During the Periovulatory Period
The local release of Ang II, ET-1, and ANP in the MDS perfusates, OVP, and JVP in five cows with LH surge and two cows without LH surge are shown in Figure 4. The follicular release of Ang II was low during the pre-LH surge period, rose (P < 0.05) at the beginning of the increase in the plasma LH surge, and then remained stable during the period of the experiment. On the other hand, ET-1 release dropped when the plasma LH started to increase (P < 0.05). Before the LH surge, the levels of Ang II in the OVP and JVP were similar. The concentration of Ang II in the OVP rose after the peak of the LH surge (P < 0.01). The highest concentration of Ang II (P < 0.001) in the OVP was observed between 24–48 h when multiple ovulation was expected to occur. During this period the Ang II concentrations in the JVP were lower than those of OVP (P < 0.01 to P < 0.001). However, the Ang II concentration increased (P < 0.05) in the JVP after the peak of the LH surge (Table 1). The ET-1 and ANP concentrations in the OVP slightly increased from 0 to 24 h after the LH surge (P < 0.05).
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Relationship Between Ang II and PGF2 Concentrations in Ovarian Venous Plasma
In cows with an LH surge, the peak in PGF2 was almost coincident with the peak in Ang II in the OVP of two cows at the expected time of ovulation (Fig. 5). These acute peaks were not detected in the remaining three cows, but clear increases were observed in the concentrations of PGF2 and Ang II in the OVP.
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DISCUSSION
The results of the present study clearly demonstrate that the theca layer of bovine mature follicles produces and releases Ang II, ET-1, and ANP. In addition, the results also indicate that Ang II and PGF2 concentrations acutely increase in the OVP around the time of ovulation in the cow. Among these three vasoactive peptides analyzed in the present in vivo study, only Ang II showed an increase in the secretion within the theca layer of mature follicle that was followed by an acute increase in OVP; ET-1 and ANP levels in OVP remained relatively stable. However, if we consider the slight changes in ET-1 and ANP in the MDS perfusate or OVP from 0 to 24 h after the LH surge, these peptides, together with Ang II may take part in the cascade of the ovulatory process.
Implantation of the MDS capillaries into the follicular wall did not disrupt steroid secretion, as evidenced by changes in the local follicular releases of E, A, and P detected in the present MDS study and the similar study in pigs by others [26]. In addition, OVP and JVP concentrations of Ang II and ANP during the first 24 h after the surgery were not different, and then each peptide showed different changing patterns after the LH surge. Although we can not exclude the possibility that the microdialysis capillaries would alter normal release of these peptides from the surrounding tissues, the above findings suggest that the surgery did not affect severely the local release of peptides. The results also confirmed that the secretory products of both theca and granulosa cells diffuse into the dialysis tubing. The changes in the plasma steroid concentrations were comparable with previous results obtained during the periovulatory period in superovulated cows [31]. Progesterone concentration began to increase in the MDS perfusates as well as in the OVP at 24 h after the peak of the LH surge, indicating the luteinization of the granulosa cell before ovulation. In contrast, in the two cows without an LH surge, the levels of P in the MDS as well as in the OVP remained low, indicating that ovulation and subsequent CL formation did not occur. In fact, this was confirmed by ovariectomy at the end of the experiment.
During the ovulatory process after the LH surge, there are prominent changes in the regional blood flow of the follicle with a marked increase in the flow to the base of the follicle and a concomitant decrease in blood flow to the apex [32]. However, due to technical limitations, we implanted most of the MDS capillaries into the lateral part where, in the human follicle, the blood flow was shown to remain unchanged [32]. Therefore, it is possible that we could not detect sufficiently drastic changes in the release of local vasoactive peptide that may directly reflect the site-specific blood flow in the follicle around the time of ovulation.
Injection of an ovulatory dose of hCG has been reported to induce the expression of cyclooxygenase (COX-2) in the granulosa cells of bovine preovulatory follicles [33]. This increase in COX-2 expression was followed by a drastic increase of PG concentrations in the follicular fluid starting at 20 h after the hCG injection [33]. The present MDS study provides further in vivo evidence that a local PGF2 secretion both in the follicular wall and OVP rapidly increases at the expected time of ovulation. The presence of receptors for PGF2 (PGF2-R) in the granulosa and theca cells of bovine preovulatory follicles suggests that their ovulatory action is a receptor-mediated process [34].
The extracellular concentrations of Ang II, ET-1, and ANP in the theca layer of the present cows were calculated to be around 2 ng/ml, 0.7 ng/ml, and 20 ng/ml, respectively, if the concentrations of these peptides in the perfusate and the transfer capacity of the MDS membrane are considered. Such concentrations are clearly much higher than those in the plasma (see Table 1). These findings support the concept that mature follicles are sites of Ang II, ET-1, and ANP production. These vasoactive peptides produced at the follicular levels may play physiological roles in the control of the local changes in the blood flow as observed in the human ovulatory follicle [32] as well as in the modulation of steroidogenesis and PG production in an autocrine and/or paracrine manner [18]. It is interesting to note that in the present study, the Ang II concentrations in the perfusate of nonovulatory follicles were twofold higher than that of preovulatory follicles. It has been reported that the concentration of renin increases in atretic bovine follicular fluid [35].
Several studies have described the possible role of Ang II in the regulation of ovarian function in human, rat, rabbit, and cow [7, 18, 36, 37]. Such regulations include follicular angiogenesis [38], atresia [35, 39], steroidogenesis [40], oocyte maturation, and ovulation [6]. The Ang II binding capacity of ovarian follicular cells varied with the animal species and developmental stage of the follicle. In the cow, the expression of the Ang II receptor positively correlated with follicular size [20]. Additionally, in the bovine theca cell cultures, LH up-regulated Ang II receptor expression via a cAMP-dependent mechanism [21]. These findings suggest that the follicular renin-angiotensin system is up-regulated toward ovulation that is triggered by the LH surge.
Unlike the concentration of Ang II in the follicular wall [26, the present study], the concentration of Ang II in the OVP drastically increased after the endogenous LH surge. This increase was reflected in the JVP at 24–48 h after the LH surge. The result is consistent with the report of cyclic changes in the plasma concentration of prorenin in women [41]. However, the plasma concentration of Ang II was 100-fold lower than the concentration found in the extracellular fluid of the theca layer. Thus, Ang II concentration in the OVP is too low to elicit a significant effect on follicular cells in an autocrine/paracrine manner. Consequently, we assume that the observed peak of Ang II in OVP was the result of mechanical stress of follicle rupture but was not the cause of ovulation. On the other hand, the high concentration of Ang II found in the theca layer increased with the rise of plasma LH (LH surge), and it remained high for the rest of the experimental period. This increase in Ang II secretion in the follicular wall may represent the LH surge-triggered cascade that leads to ovulation. We recently demonstrated a dynamic interaction among Ang II, ET-1, and ANP, and that these peptides stimulate PG secretion and modify the secretion of steroids using an MDS of the bovine mature follicle in vitro [18]. In that study, Ang II stimulated ET-1 release and ET-1 stimulated ANP release from bovine mature follicles. Thus, ET-1 and ANP may play a permissive but modulating role in the local control of ovarian Ang II production.
Endothelial cells appear to be the major source of ovarian Ang II. This peptide is possibly released from endothelial cells to the basal side of the endothelium. From there it would pass to the theca interna and granulosa layer and would thereby modify membrane permeability, PG biosynthesis, and steroidogenesis in follicular cells (endothelial cells, granulosa cells, and theca cells). In support of this idea, our previous study revealed that bovine microvascular endothelial cells derived from the developing CL have the capacity to convert Ang I to Ang II and that several endocrine and paracrine/autocrine factors affect Ang II production [42]. In addition, no Ang II was detected in the culture medium of bovine granulosa and theca cells [43], even in the presence of the precursor Ang I.
The peak of PGF2 was almost coincident with the peak of Ang II in the OVP of two cows at the expected time of ovulation. Angiotensin II is known to stimulate PG synthesis in both central and peripheral tissues by the action on specific phospholipase [44, 45]. In the present study, the Ang II concentration in the OVP remained at high levels even after ovulation. Our previous study reported a high correlation between the actions of Ang II and PGF2 in the promotion of P release from the early CL [46]. In the same study, Ang II and PGF2 productions were found to be greater in the early CL than in the mid CL [46]. These changes were reflected in the OVP concentrations in another in vivo observation [47]. Thus, Ang II together with PG could play an important role in the local increase of P secretion and induce angiogenesis during CL development.
In conclusion, the present results demonstrate for the first time the local release of Ang II, ET-1, and ANP from the bovine mature follicle in real-time in vivo and show that Ang II and PGF2 concentrations in the OVP acutely increase around the time of ovulation. The overall results support the concept of a local functional ET-Ang-ANP system in the bovine mature follicle that may be involved in the ovulatory process.
ACKNOWLEDGMENTS
The authors 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, and Fresenius AG, St. Wendel, Germany for the microdialysis capillary membrane.
FOOTNOTES
1 This study was supported by Grants-in-Aid for Scientific Research (11660276 and 12556046) and the Japan-Germany joint research project of the Japan Society for the Promotion of Science (JSPS), the Novartis Foundation (Japan) for the Promotion of Science, and the German Research Foundation (Scha 254/14-1). T.J.A is a postdoctoral fellow supported by JSPS, S.K. and K.H. were supported by H. Wilhelm Schaumann Stiftung, and A.M. was supported by Alexander von Humboldt Stiftung. 
2 Correspondence. FAX: 81 155 49 5462; akiomiya{at}obihiro.ac.jp
3 Current address: T.J. Acosta, Dept. of Animal Science, Obihiro University of Agriculture and Veterinary Medicine, Obihiro 080-8555, Japan.
Accepted: June 2, 2000.
Received: March 7, 2000.
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 E. V. Bokal, H. M. Vrtovec, I. V. Klun, and I. Verdenik Prolonged HCG action affects angiogenic substances and improves follicular maturation, oocyte quality and fertilization competence in patients with polycystic ovarian syndrome Hum. Reprod., June 1, 2005; 20(6): 1562 - 1568. [Abstract] [Full Text] [PDF]
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N. Levy, M. Gordin, M. F. Smith, O. U. Bolden-Tiller, and R. Meidan Hormonal Regulation and Cell-Specific Expression of Endothelin-Converting Enzyme 1 Isoforms in Bovine Ovarian Endothelial and Steroidogenic Cells Biol Reprod, April 1, 2003; 68(4): 1361 - 1368. [Abstract] [Full Text] [PDF]
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S.-i. Kobayashi, T. J. Acosta, T. Ozawa, K. Hayashi, B. Berisha, M. Ohtani, D. Schams, and A. Miyamoto Intraluteal Release of Angiotensin II and Progesterone In Vivo During Corpora Lutea Development in the Cow: Effect of Vasoactive Peptides Biol Reprod, January 1, 2002; 66(1): 174 - 179. [Abstract] [Full Text]
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