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Biology of Reproduction 61, 1487-1491 (1999)
©Copyright 1999 Society for the Study of Reproduction, Inc.

Articles

Hormonal Control of Urokinase Plasminogen Activator Secretion by Sheep Ovarian Surface Epithelial Cells1

Jenifer Murdocha, Edward A. Van Kirka, and William J. Murdoch2,a

a Department of Animal Science, University of Wyoming, Laramie, Wyoming 82071


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Secretion of urokinase plasminogen activator (uPA) by ovarian surface epithelium (OSE) adjacent to the preovulatory ovine follicle has been implicated in apical tissue degradation and follicular rupture. In vitro experiments were designed to test the hypothesis that uPA release by OSE is under direct hormonal control. Epithelial cells were isolated from the ovarian surface of sheep using a polytetrafluorethylene scraper designed to dislodge adherent cells from culture flasks. Amidolytic cleavage of a uPA-specific chromogen (carbobenzoxy-L-{gamma}-glutamyl [{alpha}-ot-but]-glycyl-arginine-p-nitroanilide monoacetate) was used as a measure of enzymatic bioactivity in OSE-conditioned incubation media. Secretion of uPA by OSE suspensions from proestrous ewes was stimulated by exposure (2 h) to a preovulatory surge-like concentration of LH. OSE cells obtained during the luteal phase or anestrus were not responsive to LH. Baseline rates of uPA secretion and expression of estradiol receptors (in situ immunofluorescence detection) were not affected by reproductive status. Induction of uPA secretion by anestrous OSE was attained after priming (6 h) with estradiol-17ß; responsiveness was attributed to gonadotropin receptor (ligand binding) up-regulation. Monolayers of OSE established on polyethylene membranes secreted uPA predominately in a basal (i.e., toward the substratum) direction. We suggest that OSE in juxtaposition with the (hyperemic) wall of the preovulatory follicle is perfused by surge levels of LH, invoking uPA release into underlying ovarian tissues.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The mammalian ovary is encased by a simple cuboidal to low pseudostratified columnar layer of epithelial cells. Ovarian surface epithelium (OSE) is supported along the tunica albuginea by a basal lamina and is held together laterally by desmosomes and gap/tight junctions. Outgrowth of a follicle selected to ovulate brings it into close contact with the OSE [1]. In some species, ovulation is restricted to an ovarian depression (fossa) covered by prototypical (coelomic mesothelial) surface epithelium [2].

A role for the OSE in the process of ovulatory follicular rupture has been debated for many years. There is morphological evidence that proteolytic enzymes liberated from OSE aid in degradation of the connective tissue matrices of the tunica albuginea and follicular theca [3]. Recent studies indicate that the OSE contiguous with preovulatory ovine follicles secretes urokinase plasminogen activator (uPA). Interstitial zymogen is consequently converted to plasmin, which activates latent collagenases. Plasmin also liberates the apoptosis-inducing tumor necrosis factor (TNF)-{alpha} from its transmembrane anchor along theca endothelium. Collagenolysis and cellular deletion hence lead to weakening of the apical ovarian wall, stigma development, and ovarian rupture. Indeed, ovulation was inhibited in ewes by surgical removal of OSE or by intrafollicular injection of uPA antibodies, {alpha}2-antiplasmin, or TNF-{alpha} antibodies [4–6].

Regulatory mechanisms of uPA secretion by OSE have not been elucidated. It has been hypothesized that uPA is released from estrogen-primed OSE in response to LH. The close proximity of OSE to the wall of the preovulatory follicle affords preferential surge gonadotropic exposure due to a marked increase in the permeability of the theca vascular wreath [7]. Steroid hormone and gonadotropin receptors are present in some carcinogenic lines of human OSE [8, 9]. Moreover, estradiol-17ß potentiates LH receptor induction in granulosa cells [10].

The initial objectives of this investigation using primary incubates of sheep OSE were to determine whether uPA secretory responsiveness to LH is affected by reproductive state and estradiol-17ß exposure. We then analyzed the directional secretion of uPA in polarized cells. Finally, estrogen and LH receptor dynamics in OSE were elucidated.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Experiments were performed with the approval of the University of Wyoming Animal Care and Use Committee. Ovaries of western-range ewes were obtained when animals were killed (i.v. Beuthanasia; Schering-Plough Animal Health, Kenilworth, NJ). Reagents were purchased from Sigma Chemical Co. (St. Louis, MO) unless indicated otherwise.

Preliminary Experiments: Cell Isolation and Suspension Incubation

Six ovaries were used for these studies. To avoid contamination of the ovarian surface with blood cells, the vascular pedicle was clamped with a hemostat and wrapped in gauze at ovariectomy. Epithelial cells were removed aseptically from the surface of ovaries using a polytetrafluorethylene scraper designed to dislodge adherent cells from culture flasks (Becton Dickinson, Franklin Lakes, NJ). Cells were rinsed from the edge of the scraper with 0.05 ml RPMI-1640 medium (- phenol red; + 10% fetal calf serum, 10 µg/ml insulin, 125 U/ml penicillin, and 50 µg/ml streptomycin), incubated (0.5-ml microfuge tube) in a humidified CO2 atmosphere for 6 h at 37°C, and pelleted by centrifugation (12 000 x g, 10 min). Cellular integrity (plasma membrane permeability) before and after incubations was determined by trypan blue exclusion.

To validate the efficiency and selectivity of the isolation technique, ovarian tissues were examined for OSE and surface basement membrane fidelity. Ovaries were fixed in Histochoice (Amersco, Solon, OH), embedded in paraffin, serially sectioned (6-µm thickness), stained with hematoxylin and eosin, and examined by light microscopy (Olympus BH-2 with photography; Tokyo, Japan).

Effect of LH on uPA Secretion by OSE: Relationship to In Vivo Endocrine Status

Surface cells from each ovary of 3 luteal-phase (Day 10 of the estrous cycle), 3 follicular-phase (36 h after a luteolytic injection of PGF2{alpha} on Day 14; [11]), and 3 anestrous ewes were incubated for 2 h in either the absence or presence of ovine LH (5 ng NIH S-18/0.05 ml; Bethesda, MD). The in vitro dose of LH was representative of circulatory preovulatory peak concentrations [12]. Supernatants were harvested from cells and assayed for uPA. Cellular pellets were analyzed for protein (Bio-Rad, Hercules, CA).

In Vitro Influence of Estradiol-17ß on LH Induction of uPA Secretion

OSE cells of anestrous ewes (n = 6) were incubated or were not with estradiol-17ß (10 ng/0.05 ml, 0.2% ethanol, 6 h). The dose of estradiol-17ß was indicative of proestrous follicular fluid concentrations [13]. Media were replaced with RPMI-1640 containing LH (5 ng), and cells were incubated for an additional 2 h. Supernatants and cells were assayed for uPA and protein, respectively.

Directional Secretion of uPA

Surface ovarian cells from each of 4 anestrous ewes were seeded onto semipermeable polyethylene terephthalate transwell inserts (1-µm pore size; 24-well plate; Becton Dickinson) and cultured (RPMI-1640 with supplements as described above) to confluent monolayers (48 h). Cells were then either exposed or not exposed to estradiol-17ß, and then to LH, as indicated for the preceding study. Conditioned media for uPA analysis were collected from the upper (supernatant) and lower (infranatant) chambers of the bicameral inserts. Cells for protein assessments were removed from membranes by vigorous rinsing (5 times with 1 ml PBS).

Direct uPA Assay

Amidolytic cleavage of a uPA-specific chromogen (carbobenzoxy-L-{gamma}-glutamyl [{alpha}-ot-but]-glycyl-arginine-p-nitroanilide monoacetate; American Diagnostica, Greenwich, CT) was used to measure urokinase bioactivity in cell-conditioned incubation media [14]. Samples (50 mul) were mixed in 96-well microplates with reaction buffer (50 µl 50 mM Tris with 0.01% Tween 80 and 10 KIU sterile aprotinin, pH 8.8) and substrate (50 µl, 2.5 mM) for 18 min at 25°C. Release of free chromophore (p-nitroanilide) was determined spectrophotometrically (405 nm). Standard reference curves were prepared using low molecular weight human uPA (160 000 IU/mg; American Diagnostica). The linear assay range was 1–32 IU. Different dilutions of a pooled conditioned medium yielded results parallel to the standard curve, and substrate metabolism was not affected by the addition of tissue (t)-type PA (32 IU; American Diagnostica). Coefficients of variation were < 8%. Data are expressed as IU uPA/mg cellular protein.

Hormonal OSE Receptors During Divergent Reproductive States

Ovaries of each of 3 luteal-phase, 3 follicular-phase, and 3 anestrous ewes were hemisected. Surface cells from one portion of each ovary were removed for LH receptor analysis. Estrogen receptors in OSE were monitored in paraffin-embedded sections of counterpart tissues.

Dislodged OSE were transferred onto microscope slides treated with subbing solution (0.025% chromium potassium sulfate, 0.25% gelatin) and air dried. Membrane receptors for LH were detected using fluorescein isothiocyanate (FITC)-conjugated (FluroTag Kit according to the instructions of the manufacturer) to purified hCG (5 ng/0.05 ml PBS, 30 min, 37°C). Slides were washed in two changes of PBS and coverslipped. Images of discrete groups of cells (10 per sample selected at random) were captured (x200; Olympus BH-2 equipped with a reflected light fluorescence attachment and Pixera [Los Gatos, CA] 1.2-million-pixel digital camera interface) and categorized (luminance intensity: 0–5) by computer-assisted analysis (Optimas, Bothell, WA). Negative controls were carried out using follicular-phase OSE (n = 4) coincubated with 100-fold excess unlabeled hCG.

Estrogen receptors (ER{alpha}) were localized using a species cross-reactive mouse monoclonal antibody raised against amino acids 120–170 mapping within the N-terminal domain (C-314; Santa Cruz Biotechnology, Santa Cruz, CA); the antibody specifically recognized a band (~65 kDa) corresponding to ER on a Western blot of sheep ovarian tissue. Tissue sections were incubated for 30 min with anti-ER{alpha} (0.2 µg/ml PBS with 1.5% normal goat serum) and washed in two changes of PBS. Immune complexes were detected with a secondary goat anti-mouse IgG-FITC (F 4143; 1:80, 10 min; 2 times PBS wash). Negative control reactions (n = 4; follicular-phase OSE) were performed in the absence of primary antibody. Fluorescence intensities of cells (4 chosen randomly from each of 5 different tissue sections of each specimen; x1000) were ascertained by computer analysis.

Effect of Estradiol-17ß on LH Receptor Expression

Surface epithelia of ovaries of 3 anestrous ewes were incubated in the absence or presence of estradiol-17ß (10 ng/0.05 ml, 6 h) and then assessed as previously indicated for relative hCG-FITC binding.

Statistical Analyses

Assignments to treatments/morphometric analyses were made at random. Subsample data were averaged. Mean contrasts were made by ANOVA and protected least significant difference or Student's t-test. Differences were considered significant at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Histological examination of ovarian sections indicated that in all specimens, epithelial cells were completely removed (~75 000 per ovary) from the surface basement membrane (Fig. 1). Cellular viabilities were > 80% after removal, incubation, and pelleting.



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  		FIG. 1. A representative photomicrograph of a tissue section through the ovarian surface effaced of epithelium is illustrated in A. For comparison in B, an epithelium-intact (unmanipulated ovary) tissue section is shown

Secretion of uPA by OSE isolated during the follicular phase was stimulated by LH. Cells recovered during the luteal phase or the anestrous season did not respond to LH and release uPA. Incubation of anestrous OSE that were primed with estradiol-17ß and then challenged with LH secreted greater quantities of uPA than cells that were not pretreated (Fig. 2).



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  		FIG. 2. A) Effects of LH on secretion of uPA by OSE obtained from ewes during the follicular phase (FP), luteal phase (LP), and anestrous season (AS). B) Responses to LH of anestrous OSE pretreated or not with estradiol-17ß (E2). Means ± SE are plotted. An asterisk indicates significant (P < 0.001) elevations

When OSE were seeded onto permeant membranes, allowed to form a confluent monolayer, primed with estradiol-17ß, and then treated with LH, uPA was secreted mainly in a basal direction. In contrast, OSE not incubated with estradiol-17ß did not respond to LH (Fig. 3).



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  		FIG. 3. Directional secretion of uPA by polarized OSE primed with estradiol-17ß and then treated with LH. The asterisk indicates a significant (P < 0.001) increase

ER{alpha} were readily detectable within the surface epithelium; however, there were no significant alterations in immunoreactivities due to reproductive status (constitutive expression). Fluorescence intensity scores of surface epithelial cells were attenuated in negative control ovarian sections incubated with secondary detection antibody only. Follicular-phase OSE reacted strongly with FITC-hCG. Binding of conjugate to OSE isolated during the luteal phase and anestrus was negligible. Fluorescence values of follicular-phase OSE preincubated with excess hCG (negative control) were similar to those of luteal-phase and anestrous (- estradiol-17ß) cells. Receptor sites for LH were induced following treatment of anestrous OSE with estradiol-17ß (Fig. 4). The inability of luteal-phase and anestrous OSE to secrete uPA in response to LH (Fig. 2) was therefore related to a lack of receptor detection.



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  		FIG. 4. A) Alterations in OSE estrogen and LH receptors due to stage of the reproductive cycle. B) Summary of negative controls. C) The effect of estradiol-17ß on LH receptors in OSE of the anestrous season. An asterisk denotes significant (P < 0.01) increases. D) An ovarian tissue section depicting a representative OSE ER{alpha} expression morphology. E (- estradiol-17ß) and F (+ estradiol-17ß) are photomicrographs of hCG-FITC binding (LH receptors) to isolated anestrous OSE


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
To our knowledge this is the first report documenting hormonal effects on enzyme secretion by OSE. Estradiol-17ß imparted sensitivity of sheep OSE to LH-induced uPA release relevant to the proteolytic mechanism of ovulatory ovarian rupture.

It appears that estradiol-17ß causes the induction of LH receptors on OSE—akin to the applicable process in granulosa cells of preovulatory follicles, whereby FSH and estradiol-17ß interact to augment receptor expression [10]. A possible action of FSH on OSE was not obligatory, in that LH responsiveness of anestrous OSE was increased in vitro by treatment with estradiol-17ß alone.

In the sheep, uPA of OSE origin catabolizes plasminogen within a limited diffusion radius encompassing the formative site of ovulation [4]. Plasminogen activators also were elevated preferentially within the apices of preovulatory porcine [15] and rat [16] follicles. The general consensus of functional studies indicates that uPA is the primary mediator of tissue degradation and that tPA (which has an affinity for fibrin) is involved in thrombolysis [17]. Ovulation in ewes was unaffected by intrafollicular injection of tPA antibodies [4].

A critical factor in the expression of PA function is mode of localization. Secretory PA pathways of epithelial layers have been segregated into apical or basolateral domains [18]. Results of the experiment using polarized ovine OSE indicate that uPA secretion is directed in a basal orientation. The in vivo inference is that uPA is released toward the tunica albuginea. Thus, up-regulation of plasmin biosynthesis within the ovarian dome-follicular interface would afford a focal point of collagenolytic and TNF-{alpha}-mediated ovulatory tissue damage.

Follicle-associated OSE normally becomes apoptotic and is sloughed near the time of ovulation [19, 20]. Some cells along the margins of ruptured follicles that endure the (sublethal) insult of ovulation contain damaged DNA [21]. It appears that the majority of ovarian cancers arise by malignant transmutation of a surface cell that is thereby traumatized and then propagated during repair of the rupture wound [22–24]. Because uPA has been implicated in the metastatic propensity of endocrine-dependent malignancies [25–28], and estrogens and gonadotropins are putative mediators of ovarian neoplasia [8, 29], it will be pertinent to determine whether transformed OSE retain hormonal sensitivity toward uPA secretion and disease progression.

Results of this investigation indicate that LH stimulates uPA secretion by sheep OSE during the preovulatory period; nonfollicular-phase cells secrete uPA in response to LH only after pretreatment with estradiol-17ß (LH receptor expression). An understanding of the dynamics of hormonal effects on uPA secretion by OSE is applicable to the control mechanisms of ovulation (apical ovarian/follicular tissue degradation) and common epithelial ovarian cancer (invasive potential).


   FOOTNOTES
 
1 Supported by USDA-NRI grant 95–37203–2131. Back

2 Correspondence: W.J. Murdoch, Department of Animal Science, P.O. Box 3684, University of Wyoming, Laramie, WY 82071. FAX: 307 766 2355; wmurdoch{at}uwyo.edu Back

Accepted: July 20, 1999.

Received: May 3, 1999.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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