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Regular Article |
a Departments of Obstetrics and Gynecology,
b Perinatal Research Laboratories, Dairy Science, and
c Animal Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53715
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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estradiol, progesterone, prostaglandins, steroid hormones, uterus
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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120 min) increase in UBF in estrogen-treated ovariectomized sheep [6, 9–11]. During prolonged estrogen infusion, concomitant progesterone treatment did not alter the estrogen-mediated elevation in UBF [6, 12] but may redistribute UBF in favor of the caruncles, i.e., the future site of ovine placentation [12]. When both estrogen and progesterone are elevated in ovine pregnancy, the potent vasodilator prostacyclin (PGI2) is also elevated in systemic arterial and uterine venous plasma [1, 3, 13]. Phospholipase A2 (cPLA2) protein expression is only regulated in the endothelium and not the vascular smooth muscle (VSM) of uterine arteries and is increased during pregnancy but not during the ovarian cycle [14]. Cyclooxygenase 1 (COX-1) protein expression is greater in the endothelium than in the VSM of uterine arteries [15]. COX-1 protein, the key enzyme in the production of PGI2 from arachidonate, exhibits a marked increase in expression during pregnancy [15, 16] and is elevated, but to a lesser extent, during the follicular phase of the ovarian cycle in uterine artery endothelium [15]. COX-1 mRNA also is increased in uterine artery endothelial cells during pregnancy compared with nonpregnancy and in the follicular and luteal phases of the ovarian cycle compared with levels detected in ovariectomized controls [15]. However, COX-1 protein levels in the omental artery were unaltered by ovariectomy, phase of the ovarian cycle, or pregnancy [15]. In a previous study, PGI2 synthetase (PGIS) protein expression was upregulated during pregnancy in the uterine but not systemic (omental) vasculature, and PGIS expression was slightly greater in the VSM than in the endothelium [17]. Furthermore, PGIS in the endothelium of uterine arteries was increased during pregnancy compared with levels detected in ovariectomized and luteal phase sheep, whereas omental artery endothelial PGIS was unaltered by the ovarian cycle but was elevated during pregnancy. PGIS expression in the VSM was specific to the uterine arteries and only increased during pregnancy [17].
The objectives of this study were to examine the effects of prolonged treatment with progesterone in the absence and presence of estrogen on the key enzymes in uterine and systemic arteries that are involved in the production of the vasodilator PGI2. The specific aims of the current study were to determine the effects of estrogen, progesterone, and their combination on cPLA2, COX-1, and PGIS protein expression in the reproductive (uterine and mammary) and nonreproductive (renal, omental, and coronary) artery endothelium and VSM.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Mixed western breed ewes (n = 45) were ovariectomized via a midventral laparotomy as previously described [5, 7, 18], and after at least 10 days, steroid replacement therapy was begun [19]. For the estradiol-17ß (E2ß)-treated ewes (n = 10), an indwelling 19-gauge polyvinyl catheter was placed into the right ventricle via the jugular vein. Animals then received a 5 µg/kg bolus of E2ß (Sigma Chemical Co., St. Louis, MO) mixed in 3 ml (10–11% ethanol) of saline, which was then flushed through the catheter with 5 ml of saline, followed immediately by 6 µg kg-1 day-1 continuous infusion of E2ß in 0.9% isotonic saline (0.0123 ml/min) for 10 days. E2ß was dissolved in 95% ethanol and stored at 4°C at a stock concentration of 1 mg/ml. The E2ß dose and timed tissue collection was based on hemodynamic responses and blood levels of E2ß achieved in previous studies [7, 8]. For administration of progesterone (P4; n = 13), 3 controlled internal drug release (CIDR) implants with 0.9 g P4 (Carter Holt Harvey, Auckland, New Zealand) were placed into the vagina of ovariectomized ewes for 10 days. For combined treatment (P4 + E2ß; n = 12), both E2ß infusion and CIDR P4 implants were used. Control ewes (Veh; n = 10) received vehicle (ethanol in saline) infusion and/or blank CIDR implants. With this protocol, P4 levels in systemic circulation were elevated in ewes treated with P4 and P4 + E2ß compared with luteal phase and control ewes (Time 0 for all animals: control = 0.06 ± 0.04 ng/ml; luteal = 2.44 ± 0.35 ng/ml; P4 = 3.53 ± 0.27 ng/ml; P4 + E2ß = 3.16 ± 0.69 ng/ml). P4 levels during E2ß treatment were 0.20 ± 0.16 ng/ml and were not different from Veh values (0.18 ± 0.10 ng/ml) or the Time 0 prehormone control levels. These P4 levels are slightly lower than those observed by Scudamore et al. [20] with the use of 3 CIDR implants, possibly because of differences in the animals' diets. E2ß levels during E2ß and combination treatments were elevated above those of controls but were variable because of assay variability (data not shown). The ewes were killed with pentobarbitol sodium, which was given i.v. (
50 mg/kg). Procedures for animal handling and protocols for experimental procedures were approved by the University of Wisconsin-Madison Research Animal Care Committees of both the Medical School and the College of Agriculture and Life Sciences and followed the recommended American Veterinary Medicine Association guidelines for euthanasia of laboratory farm animals [21].
Isolation and Preparation of Blood Vessels
We previously described and validated a rapid isolation procedure to obtain endothelium-derived proteins devoid of major VSM contamination [8]. Uterine, mammary, omental, renal, and coronary arteries were excised, placed in PBS (8 mM sodium phosphate, 2 mM potassium phosphate, 0.15 M NaCl, pH 7.4; Sigma Chemical Co., St. Louis, MO), dissected free of connective tissue, and rinsed free of blood. Portions of each artery type were opened longitudinally and the endothelium/tunica intima was gently scraped (3–6 times) from the artery and placed into lysis buffer (50 mM Tris, 0.15 M NaCl, 10 mM EDTA, pH 7.4, plus 0.1% Tween 20, 0.1% ß-mercaptoethanol, 0.1 M phenylmethylsulfonyl floride, 5 µg/ml leupeptin, and 5 µg/ml aprotinin; Sigma) using a curved-end spatula as previously described [8, 18]. The remaining scraped vessel was rubbed with a wet cotton swab, and any remaining adventitia was extensively removed before the denuded artery (VSM) was placed in lysis buffer. The endothelium-isolated proteins (Endo) and denuded arteries (VSM) were snap frozen in liquid nitrogen immediately upon collection and were stored at -20°C.
Preparation of Tissues for Western Immunoblot Analysis
VSM from uterine, mammary, omental, renal, and coronary arteries was homogenized in lysis buffer and then sonicated. Endo from the same arteries were sonicated. After centrifugation (250 x g for 10 min) to remove particulate matter from vessel preparations, the protein concentrations were determined using a modified Lowry assay procedure (Bio-Rad, Hercules, CA). Known concentrations of protein (30 µg for VSM, 10 µg for Endo) were resolved on 7.5% 15-well polyacrylamide gels (Bio-Rad) with 0.1% SDS at 100 V for 1.5 h at room temperature before transfer onto Immobilon-P membranes at 100 V for 2 h. Membranes were blocked with Tris buffer (20 mM Tris basic, 500 mM NaCl, pH 7.5; Sigma) containing 0.1% Tween 20 and 5% skim milk and were then rinsed briefly with Tris buffer to remove excess milk protein. Monoclonal cPLA2 primary antibody was obtained from Santa Cruz Biotechnology (Santa Cruz, CA; 1:500 dilution), and the secondary antibody, sheep anti-mouse Fab2 (Amersham, Piscataway, NJ), was used for cPLA2 and COX-1 (1:2500 and 1:5000 dilutions, respectively). The primary COX-1 monoclonal antibody was from Cayman Chemical Company (Ann Arbor, MI; 1:3000 dilution). The primary PGIS polyclonal antibody (raised in rabbits) was from Cayman (1:30 000 dilution). The secondary antibody for PGIS antiserum was a donkey anti-rabbit Fab2 serum (Amersham; 1:2500 dilution). Primary antibody was dissolved in Tris buffer containing 1% BSA and Tween 20, and the secondary antibody was dissolved in Tris buffer with Tween 20 and 0.5% skim milk. Primary antibody incubations were for 2 h at room temperature, and secondary antibody incubations were for 1 h with one 15-min and three 5-min washes with Tris buffer and Tween 20 after each incubation period. The membrane was probed as recommended by the manufacturer (Amersham) using the enhanced chemiluminescence kit and exposure to Hyperfilm (5 min for cPLA2, 2 min for COX-1, and 1 min for PGIS). The relative level of cPLA2, COX-1, and PGIS in each sample was determined using a scanning transmission densitometer (model 670; Bio-Rad) coupled with Molecular Analysis software (v. 1.5, Build 468; Bio-Rad).
Statistical Analysis
Differences in treatment groups (Veh, P4, E2ß, and P4 + E2ß) for each vessel were analyzed using a one-way ANOVA and a Student t-test. Differences were considered significant at P < 0.05. Data are expressed as percentage of vehicle control for the vehicle lanes on each individual blot.
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RESULTS |
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In the uterine artery Endo, cPLA2 and COX-1 were increased in a similar fashion with E2ß and P4 + E2ß treatments. Although both cPLA2 and COX-1 levels were significantly increased in the uterine artery endothelium only with combination treatments, the results of the combination treatment were not different from those of E2ß alone (representative blots shown in Fig. 1; densitometry data shown in Fig. 2). Uterine artery endothelial PGIS was significantly increased (P < 0.05) only with E2ß treatment, but P4 appeared to inhibit this E2ß-induced rise in PGIS levels. In renal artery endothelium, cPLA2 was not altered by any hormone treatment, but COX-1 showed a trend toward increasing with both P4 and the combination treatment (Fig. 3; P = 0.08). PGIS was increased in renal artery endothelium with E2ß (Fig. 3) only in comparison to the combination treatment. In the coronary artery endothelium, cPLA2, COX-1, and PGIS were not altered with any hormone regimen (Fig. 4). In the omental artery endothelium, cPLA2 was at or below detectable limits and COX-1 and PGIS were not altered by hormone treatment (data not shown). In mammary artery endothelium, the levels of cPLA2 and COX-1 protein was undetectable and PGIS was unaltered (data not shown).
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Expression of cPLA2, COX-1, and PGIS in the Uterine Microvasculature
Expression of cPLA2 and COX-1 was very difficult to detect in the endometrial, caruncular, and myometrial microvessels of the uterus. However, PGIS expression was quantifiable in all uterine microvessels. P4 treatment appeared to slightly elevate PGIS protein expression in the caruncular and endometrial microvessels, and E2ß treatment slightly elevated PGIS in the myometrial microvessels (Fig. 5); however, none of these changes were significant.
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Expression of cPLA2, COX-1, and PGIS in the VSM
Expression cPLA2 protein in the VSM was not altered by hormone treatment in the uterine artery and was at or below detectable levels in mammary, omental, renal, and coronary arteries. COX-1 expression was not detectable in the VSM of any artery type studied. PGIS expression was increased (P < 0.05) with P4 treatment in the uterine, mammary, omental, and renal artery VSM (Figs. 6 and 7). E2ß treatment also increased PGIS expression in uterine and omental artery VSM; mammary artery VSM PGIS tended to be increased, but this difference was not significant. The combination treatment increased PGIS only in the uterine artery VSM. Coronary artery VSM PGIS was not altered by any hormone treatment.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The cPLA2 protein levels were increased only with combination steroid treatment and only in the uterine and not the systemic artery endothelium. This observation for the uterine artery endothelium directly relates to results of previous studies in which we observed elevations in cPLA2 in the uterine artery endothelium during pregnancy [14], a time when estrogen, progesterone, and PGI2 levels are elevated [2, 3, 13, 23]. However in that preliminary study, we did not detect any significant increase in cPLA2 levels in the ovariectomized steroid-treated ewes [14]. However, in the current study in which 7 additional sheep were evaluated, many of which showed greater elevations in cPLA2 during estrogen and combination treatments, significant increases in cPLA2 levels were noted (Fig. 2). We have no explanation for the animal-to-animal variability observed with cPLA2 and not the other enzymes (COX-1, PGIS) probed on the same blots. In this and our previous study, cPLA2 in omental artery endothelial and VSM and in uterine artery VSM of ovariectomized ewes showed no alterations in response to treatment with ovarian steroids. In human umbilical vein endothelial cells (HUVEC) and human umbilical smooth muscle cells (HUSMC), cPLA2 mRNA is highly expressed [24], giving further evidence that cPLA2 is present in the VSM of arteries and veins. However, based on the results of current study, cPLA2 in the VSM does not appear to be regulated by ovarian steroids. Therefore, the uterine artery endothelium appears to be a specific target for estrogen/progesterone-regulated changes in PLA2 levels. Because cPLA2 plays an important role as the hormone-sensitive step in PGI2 production, short-term minute-to-minute changes in PGI2 synthesis in response to various agonists (e.g., angiotensin II (AII), bradykinin) are likely with estrogen and progesterone combination treatment.
COX-1 was increased primarily in the uterine artery endothelium in response to estrogen and combination treatments. COX-1 mRNA is expressed in HUVEC and HUSMC [24]; however, we did not detect COX-1 protein in the uterine artery VSM. Consistent with our previous data [15], we found higher levels of COX-1 in the endothelium than in the VSM of uterine arteries. We previously determined that COX-1 protein expression in uterine artery endothelium is substantially increased during pregnancy [15, 16] and slightly but significantly increased during the follicular phase of the ovarian cycle [15]. The current data support this finding. COX-1 was significantly increased in the uterine artery endothelium when both E2ß and P4 were administered together, similar to what occurs during pregnancy when both of these steroids are elevated. However, E2ß marginally increased (Fig. 2) COX-1 levels in uterine artery endothelium; COX-1 expression was similar to that seen with combination treatment. Therefore the E2ß-induced changes in uterine artery endothelial COX-1 may be analogous to the follicular phase modest rise in this enzyme. Furthermore, our previous data showed no effect of the ovarian cycle or pregnancy on COX-1 protein expression in omental artery endothelium [15, 16]. We concur with this observation showing no difference in omental artery endothelium with hormone treatment. We have also previously reported that COX-1 mRNA in the uterine artery endothelium during the follicular and luteal phases of the ovarian cycle and pregnancy is highly correlated with protein expression levels, indicating partial regulation at the mRNA level [15, 16, 23]. Jun et al. [25] showed that in fetal pulmonary artery endothelial cells, estrogen increased COX-1 mRNA in a dose-dependent manner after 48 h of incubation and that this increase was still present at 96 h. Furthermore, they reported increases in COX-1 protein expression, which were completely blocked by the estrogen receptor antagonist ICI 182,780. We have also noted some slight effect of estrogen alone on COX-1 in the uterine artery endothelium of steroid-treated ovariectomized ewes (Fig. 2) and during the follicular phase [15], indicating the biological importance of this hormone in regulation of COX-1, the rate-limiting enzyme for PGI2 production when arachidonate is liberated. Chakraborty et al. [26] showed that COX-1 mRNA increased in the mouse uterus when either estrogen or progesterone was given, but the most dramatic increase was seen in the luminal and glandular epithelium with coinjection of the 2 hormones. However, Wu et al. [27] did not observe any measurable changes in COX-1 mRNA or protein in the uterus of sheep treated with estrogen and/or progesterone. In the baboon endometrium, COX-1 mRNA expression was faint during the late follicular phase and increased during the luteal phase; however, it then dropped off during early pregnancy [28]. In that study, COX-1 expression was completely inhibited by the use of an antiprogestin, indicating a role for progesterone in altering gene expression of COX-1 in the uterus.
PGIS protein expression was increased with E2ß treatment in the uterine artery endothelium but was attenuated by P4 given concomitantly. In contrast, in the uterine artery VSM both E2ß alone and the combination treatment increased PGIS. It is therefore possible that PGH2 synthesis from the endothelium, the main cellular source of COX-1 and PGI2 in uterine arteries [15], is providing substrate for the VSM PGIS. It is also possible that this process partly affects the specific changes in UBF or distribution in tissues noted during steroid treatments [5–7, 10–12]. PGIS was the only prostaglandin-synthesizing enzyme in the current study that was detectable in the microvasculature. Although no significant steroid-induced elevations in microvascular PGIS levels were observed, because its levels are so high it is unlikely that this enzyme is rate limiting for PGI2 production. Differences in PGIS protein expression were also noted in the mammary and renal artery VSM with P4 treatment, in uterine and omental VSM with E2ß treatment, and in the uterine VSM with the combination treatment. We have previously shown that PGIS protein expression is increased in uterine and omental artery endothelium during pregnancy and during the follicular phase only in the uterine artery endothelium [17]. Furthermore, PGIS is increased in the VSM of uterine but not omental arteries during pregnancy. The results of the current study add to this observation, showing that PGIS increased with E2ß treatment in the uterine artery endothelium (Fig. 2) and with both steroid treatments in the uterine artery VSM (Fig. 6).
Uterine vascular PGI2 production increases dramatically during pregnancy in the sheep [3], a time when both progesterone and estrogen are elevated for a prolonged period [1, 2, 13]. Furthermore, in women receiving hormone replacement therapy (oral estrogen for 12 days followed by oral noresthisterone acetate for 10 days), plasma obtained during treatment with estrogen only or with estrogen plus progestin had the capacity to increase production of PGI2 in HUVEC [29]. This finding indicates that both estrogen and progesterone in the systemic circulation can induce PGI2 production in endothelial cells. However, the levels of the 3 enzymes responsible for the PGI2 biosynthesis by the HUVEC were not examined. Previous studies have shown that estrogen administration results in increased PGI2 production by endothelium and/or VSM of several other vascular beds in cell culture [25, 30–33], although several studies including our own have shown that estrogen has no effect on PGI2 production by uterine artery explants [22, 34] or HUVEC [35]. Because all of the above studies were performed under various cell culture/tissue explant conditions using different media, cell types from divergent species, dose responses, and time responses, it is difficult to interpret the apparent discrepancies in PGI2 synthesis. For example, not all researchers exclusively used culture medium free of phenol red, which is known to have estrogenic properties, nor were all the cell cultures grown in fetal bovine serum that had been charcoal stripped to remove all estrogen. However, Chang et al. [30,31] showed that in vitro stimulation of PGI2 by E2ß in rat aortic VSM cells is due to induction of COX-1 and to PGIS activities but not phospholipase activity. Estrogen has also been shown to increase COX-1 and PGIS expression in HUVEC culture [36]. Our study was performed with animals treated in vivo, indicating a possible physiologic role for the differential regulation of these 3 enzymes in various vascular beds and for cells types giving rise to differential responses under varying conditions.
Although the results of the present study clearly demonstrate differential regulation of the protein expressions of the 3 key enzymes in the cascade of the production of PGI2 under different ovarian steroid conditions in uterine vs. systemic vascular beds, we did not investigate the specific activity of these key enzymes. Protein expression does not always indicate enzyme activity; therefore, expression may be altered even when activity of the enzyme is not, or vice versa. This hypothesis is supported by our recent studies utilizing uterine artery endothelial cells from pregnant and nonpregnant ewes, in which we have shown that ATP and vascular endothelial growth factor (VEGF) induce increased PGI2 production in cells from nonpregnant ewes, but in cells from pregnant sheep AII, ATP, bovine fibroblast growth factor (bFGF), and VEGF all increase PGI2 production [23]. Furthermore, AII, ATP, bFGF, and VEGF all increase extracellular signal-regulated kinase phosphorylation [23] in cells from pregnant ewes, indicating the possibility that factors present during pregnancy but not evaluated in the current study may alter signaling mechanisms. It is not known whether these signaling pathways can also regulate long-term basal expression of the enzymes involved in the synthesis of PGI2.
A major finding of the present study is that the basal expression levels of the 3 PGI2-synthesizing enzymes, which is a measure of the constitutive PGI2 producing capacity, are differentially regulated by estrogen and/or progesterone in uterine vs. systemic artery endothelium or VSM. We have previously reported [6, 7] that blood flow to other nonuterine organs such as the heart is increased in response to estrogen; however, in the current study, unlike the uterine artery, we did not observe changes in the 3 enzymes studied, suggesting a role for another vasodilator. These data implicate interactions between nitric oxide (NO) and PGI2 in controlling blood flow in the uterine, coronary, and/or other systemic vascular beds upon steroid hormone administration. In this regard, we have recently shown that NO is increased in the systemic circulation when ewes are treated with progesterone and steroid combinations and that increases in NO synthase (eNOS) protein expression in the uterine, but not the systemic artery endothelium, were noted with all 3 ovarian steroid hormone treatments [19]. This finding suggests that NO may be the primary vasodilator in the uterine vasculature and that PGI2 production may mainly be necessary when NO is inhibited in particular vascular beds. Conversely, elevations in uterine artery eNOS and NO may partially regulate the rises in cPLA2 and COX-1 noted during E2ß and combination hormone treatment in the current study. It is also possible that differences in the estrogen receptor (ER) or progesterone receptor densities or their isoforms (ER
vs. ERß) could account for the differential response of the 3 enzymes in the reproductive vs. the nonreproductive vascular beds. In this regard, we have observed the presence of both ER and ERß protein and mRNA in uterine artery endothelial cells in culture (unpublished results). To our knowledge, there have been no other studies in which progesterone receptors in uterine vs. systemic artery endothelium or VSM have been evaluated. It remains to be determined what mechanisms regulate the differential basal levels of the 3 PGI2-synthesizing enzymes in uterine vs. systemic artery endothelium and/or VSM during ovarian hormone administration.
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FOOTNOTES |
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1 This work was supported in part by National Institutes of Health grants HL49210, HD33255, HL57653, HL56702, and HD38843. This study was completed in partial fulfillment of an M.S. degree (H.L.R.) in the Endocrinology-Reproductive Physiology Program (www.erp.wisc.edu). 
2 Correspondence: Ronald R. Magness, Department of Obstetrics and Gynecology, University of Wisconsin, Perinatal Research Laboratories, 7E Meriter Hospital, 202 S. Park St., Madison, WI 53715. FAX: 608 257 1304; rmagness{at}facstaff.wisc.edu
Accepted: September 7, 2001.
Received: March 9, 2001.
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by uterine arteries from postmenopausal women. Am J Obstet Gynecol 1989; 161:1677-1681[Medline]This article has been cited by other articles:
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