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DEVELOPMENTAL PHYSIOLOGY AND PREGNANCY
-Estradiol downregulates tissue angiotensin-converting enzyme and ANG II type 1 receptor in female rats
Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
Submitted 31 August 2004 ; accepted in final form 15 November 2004
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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-estradiol (E2) on the cardiovascular system may be mediated, at least in part, by its modulation of local tissue renin-angiotensin systems (RAS). We assessed two critical components, angiotensin-converting enzyme (ACE) and ANG II type 1 receptor (AT1R), in the heart, lung, abdominal aorta, adrenal, kidney, and brain in four groups of female Wistar rats (n = 5–6/group): 1) sham ovariectomized, 2) ovariectomized (OVX) treated with subcutaneous vehicle, 3) OVX treated with 25 µg/day (regular) E2 subcutaneously, and 4) OVX treated with 250 µg/day (high) subcutaneous E2 for 2 or 5 wk. After 2 wk, plasma ACE activity was not altered by OVX, but it was 34–38% lower in OVX + regular E2 and OVX + high E2 rats compared with sham OVX rats, and these decreases were no longer present after 5 wk. After 5 wk, OVX alone increased ACE activity and binding densities, and AT1R binding densities by 15–100% in right ventricle, left ventricle (LV), kidney, lung, abdominal aorta, adrenal and several cardiovascular regulatory nuclei in the brain. These effects were, for the most part, prevented by regular E2 replacement and were reversed to decreases by high E2 treatment. This regulation of tissue ACE and AT1R is significant as the activity of these tissue RAS contributes to the pathogenesis and/or progression of hypertension, atherosclerosis, and LV remodeling after myocardial infarction. renin-angiotensin system; ovariectomy; autoradiography
-estradiol (E2), play a major role in this cardioprotection. However, the validity of this perspective, including the efficacy of hormone replacement therapy in prolonging this cardioprotection, has been recently called into question. Both the estrogen-only and the estrogen and progestin arms of the Women's Health Initiative study were discontinued because of significant negative cardiovascular outcomes (31, 32). In light of these recent findings, further study of the biochemical mechanisms of action of E2 on the cardiovascular system in both physiological and pathophysiological states is warranted. The renin-angiotensin system (RAS) is a major endocrine, paracrine, and autocrine regulator within the cardiovascular system. Its main effector peptide ANG II acts at the ANG II type 1 receptor (AT1R) to regulate many cardiovascular processes. Although the classical function of the angiotensin-converting enzyme (ACE) is to convert ANG I to ANG II, this enzyme is also involved in the catabolism of the vasodilator bradykinin and thus plays a dual role in the regulation of vasoactive peptide concentrations. In addition to its regulation of homeostatic processes, the RAS has been implicated in the initiation and/or progression of several diseases of the cardiovascular system (3). Although the classical, circulating RAS may contribute to these pathologies, it is becoming increasingly clear that local tissue RASs are also major contributors. For example, after myocardial infarction in rats, hyperactivity of the local cardiac and brain RAS contributes to progressive left ventricular dysfunction that is prevented by systemic or central RAS blockade (16, 28).
Estrogens, including E2, regulate several components of the RAS. Ovariectomy (OVX) alone reduces angiotensinogen in plasma, an effect that is prevented by E2 replacement at physiological levels (7). E2 treatment of OVX rats does not affect plasma renin activity or plasma ANG II concentration (4). OVX alone increases AT1R mRNA abundance, AT1R binding density, and ACE activity in the aorta, effects that are prevented by replacement of E2 at physiological levels (19, 28). Treatment of OVX rats with E2 at physiological levels also reduces AT1R binding density in the adrenal cortex (33) and subfornical organ (SFO) in the brain (14). Treatment of OVX rats with E2 at supraphysiological levels results in decreased ACE activity in the plasma, lung, aorta, and kidney (6).
In the aforementioned studies, the effects of E2 at physiological or supraphysiological levels were measured compared with vehicle in OVX rats. Three studies (7, 19, 28) determined effects of ovariectomy alone and the effects of E2 replacement on some components of the RAS. Neither of these studies compared the effects of all four conditions: sham, OVX alone, OVX plus physiological E2, and OVX plus supraphysiological E2. Also, a cardiovascular system-wide analysis of the tissue RAS was not undertaken in these studies. Therefore, we assessed the effects of OVX (E2 deficiency) and chronic E2 replacement at physiological and supraphysiological levels on two critical components of tissue RAS, ACE and AT1R, in tissues relevant to cardiovascular regulation such as heart, kidney, abdominal aorta, adrenal, lung, and specific brain cardiovascular regulatory nuclei: SFO, organum vasculosum laminae terminalis (OVLT), paraventricular nucleus (PVN), and median preoptic nucleus (MnPO).
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METHODS |
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Ten- to eleven-week-old female Wistar rats (Charles River Breeding Laboratories, Montreal, Quebec, Canada; 200–250 g) were maintained on a 12:12-h light-dark cycle and allowed free access to normal rat chow and water. All experimental procedures were carried out in accordance with the guidelines of the Canadian Council on Animal Care and were approved by the University of Ottawa Animal Care Committee. All chemicals and reagents were purchased from Sigma (Oakville, Ontario, Canada), except where noted.
Rats were randomly placed into four groups: 1) sham ovariectomy and sham pellet implantation surgery (sham OVX, n = 12), 2) ovariectomy plus subcutaneus pellet containing vehicle (OVX + Veh, n = 12); 3) ovariectomy plus subcutaneous pellet containing 1.5 mg E2 (25 µg/day, 60-day release; Innovative Research of America, Sarasota, FL) (OVX + regular E2, n = 11), and 4) ovariectomy plus subcutaneous pellet containing 15 mg E2 (250 µg/day, 60-day release) (OVX + high E2, n = 12). The 1.5 mg E2, 60-day release pellets result in plasma E2 levels within the normal range during the estrous cycle of the rat (19). Ten times that dose (15 mg, 60-day release) was used as the "high" E2 treatment. Bilateral ovariectomies were performed under isoflurane anesthesia via a single dorsal incision, as previously described (30). Sham-operated rats underwent the same procedure, except the ovaries were exteriorized but not removed. Immediately after ovariectomy, pellets were implanted subcutaneously in the dorsal neck area via a small incision. In the case of sham OVX rats, the small incision was made, but no pellet was implanted.
Tissue Collection
At 2 (n = 6 rats/group) and 5 (n = 5–6 rats/group) wk after OVX/sham surgery, rats were euthanized by decapitation, and trunk blood was collected for measurement of plasma ACE activity. Uterine tissue was isolated from surrounding fat and weighed as a measure of estrogen status.
The abdominal aorta was isolated and cut in two; one-half was frozen in 2-methylbutane/dry ice at –40°C, and the other half was frozen in liquid nitrogen. The heart was removed, weighed, washed in ice-cold saline and cut in half laterally. The apical half was frozen in 2-methylbutane/dry ice, and the basal half was separated into right and left ventricle/septum and frozen in liquid nitrogen. The brain was removed and frozen in 2-methylbutane/dry ice, as were the left adrenal, left kidney, and lung. The right adrenal, kidney, and lung were frozen in liquid nitrogen. Tissues frozen in liquid nitrogen were kept at –80°C until assayed for ACE activity. Tissues frozen in 2-methylbutane/dry ice were kept at –20°C until ACE and AT1R autoradiography were performed.
Tissue and Plasma ACE Activity
Tissue pieces, excluding aorta were homogenized with a Polytron homogenizer (Brinkmann Instruments, Canada) in 10 volumes of buffer containing 50 mM Tris and 150 mM NaCl, pH 7.4. To minimize tissue loss, aortas were ground in the above Tris-NaCl buffer using an Ettan sample preparation kit (Amersham Biosciences, Baie d'Urfé, Quebec, Canada). After centrifugation at 16,000 g for 15 min at 4°C, the supernatant was collected and kept at –80°C until assay. The total protein in the samples was determined by the BCA method (Pierce Biotechnology, Rockford, IL) or Bradford reagent method with BSA (Pierce Biotechnology) as standard.
ACE activity was measured, as published previously (35), with minor modifications. Briefly, 40 µg of total protein or, in the case of plasma, 25 µl of a 1:15 dilution in the above Tris-NaCl buffer were preincubated at 37°C for 20 min in the presence or absence of 100 µM captopril. After incubation at 37°C for 1 h, the reaction was stopped with NaOH, and then o-phthaldialdehyde and HCl were added. Samples were centrifuged at 1,900 g at 4°C, and 325 µl of the supernatant were added to an opaque 96-well plate (Microfluor 2, VWR; West Chester, PA). His-Leu concentration was determined by measuring the fluorescence at wavelengths 360 nm excitation and 480 nm emission, using a Fluostar Galaxy fluorometer (BMG LABTECH, Durham, NC). The fluorescence of captopril-containing tubes was subtracted from those without captopril for each sample to ensure specificity of ACE activity. Activity was expressed as nanomoles His-Leu per minute per gram of protein or nanomoles His-Leu per minute per milliliter plasma. The intra-assay and interassay coefficients of variance for this assay are 3% and 8%, respectively.
AT1R Autoradiography
AT1R ligand binding was performed, as described recently (26). Briefly, cryostat serial 20-µm sections of tissue were mounted onto microscope slides. Sections were preincubated in sodium phosphate buffer containing 0.2% (wt/vol) BSA for 15 min at 20°C and then incubated in this buffer containing 0.5 mg/ml bacitracin, 0.3 µCi/ml of 125I-labeled [Sar1Ile8]ANG II (2,176 Ci/mmol, Washington State University Peptide Radioiodination Service Centre, Pullman, WA), and 10–5 M PD-123319, an AT2 receptor antagonist for 1 h. Nonspecific binding was determined by including 1 µM unlabeled ANG II. After washing, sections were air-dried and exposed to film with methylacrylate 125I standards (Washington State University Peptide Radioiodination Service Centre). Using AIS/C image analysis software (Imaging Research; St. Catherines, Ontario, Canada), we quantified the relative optical density within each tissue by densitometry. Specific binding density was determined by subtraction of nonspecific binding from total binding density and was expressed as femtomoles per milligram wet weight of tissue. The densitometry quantification was performed without knowledge of experimental groups. Brain nuclei were defined according to the rat brain atlas of Paxinos and Watson (22).
ACE Autoradiography
ACE autoradiography was performed as described by Tan et al. (26), similar to AT1 receptor autoradiography. The ACE inhibitor lisinopril derivative 351A was iodinated in-house using the protocol of Chai et al. (5) and was used at a concentration of 0.3 µCi/ml (30 pM). Nonspecific binding was determined by incubating with 100 mM EDTA. ACE binding density was expressed as femtomoles per gram wet weight of tissue.
Statistical Analysis
Data are presented as means ± SE. Comparisons among groups were performed using a one-way ANOVA followed by the Student-Newman-Keuls test with SigmaStat software (SPSS, Chicago, IL). The level of statistical significance was set at P < 0.05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Ovariectomy alone increased body weight at both 2 and 5 wk post-OVX (Table 1). At 2 wk post-OVX, rats treated with regular and high E2 had significantly lower body weights compared with sham OVX rats. At 5 wk post-OVX, this difference was no longer present for OVX + regular E2 rats but remained for OVX + high E2 rats.
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As expected, ovariectomy decreased uterus wet weight (Table 1) at 2 and 5 wk post-OVX. E2 dose dependently increased both uterus wet weight and wet weight corrected for body weight at both 2 and 5 wk post-OVX. At 2 wk, uterus weights were significantly larger in OVX + reg E2 rats than sham OVX rats, an effect that did not remain after 5 wk (Table 1).
Changes in ACE and AT1R
Heart. After 2 wk, RV and LV ACE activity were unaffected by E2 status (Fig. 1A). After 5 wk, OVX alone did not affect RV ACE activity, but increased LV ACE activity and increased ACE and AT1R binding densities in the RV and LV (Fig. 1, B and C). These increases were prevented by regular E2 treatment and were reversed to decreases by high E2 treatment.
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Lung and plasma. After 2 wk, no effect of OVX alone on plasma ACE activity was noted. Activity was decreased similarly in OVX rats that received both regular and high E2 compared with OVX rats receiving Veh (Tables 3 and 4). This effect of E2 was transient, as after 5 wk, plasma ACE activity was similar in all groups. Interestingly, OVX alone decreased lung ACE activity at 2 wk post-OVX. Regular E2 prevented this change, and high E2 reversed it to an increase. Five weeks post-OVX, the pattern of ACE activity and ACE density was reversed. Similar to the trends in other tissues in the study, OVX resulted in large increases that were prevented by regular E2 and reversed to decreases by high E2.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Uterus, Body, and Heart Weights
The observed pattern of uterus weight is consistent with levels of E2 expected by each respective treatment, except for the somewhat larger-than-normal uterus weights in OVX plus regular E2 rats at 2 wk post-OVX. The increase in body weight after ovariectomy and decrease with E2 treatment is well documented (e.g., Ref. 13). Heart weights, when corrected for body weight, were significantly larger in E2-treated OVX rats compared with the other groups. This was likely an effect of reduced body weight/fat of these rats and not hypertrophy per se.
Heart
OVX alone increased RV and LV ACE and AT1R, effects prevented by treatment with regular E2 and reversed to decreases by treatment with high E2. In 1-yr-old rats, OVX alone increased LV AT1R protein levels by 20% 4 wk post-OVX, an effect reversed to a decrease by high E2 treatment (34). The effects of physiological E2 levels were not assessed. Concurrent parallel changes in -myosin heavy-chain levels and collagen I/III ratios suggest that at least in older rats, OVX/E2 may also affect cardiac structure (34). It is tempting to surmise that this modulation of the local cardiac RAS by E2 may influence hypertension-induced cardiac hypertrophy and LV remodeling after myocardial infarction.
Brain
OVX alone increased ACE densities in the SFO, PVN, and MnPO, and regular E2 treatment prevented these increases. Treatment with high E2 reversed these increases to decreases in the SFO, OVLT, and PVN. This is the first report of regulation of brain ACE by OVX/E2. OVX alone increased AT1R densities in the SFO, PVN, and MnPO, effects prevented by regular E2. High E2 reversed the increases in AT1R in the SFO and PVN to decreases. Estradiol benzoate treatment (EB; 10 µg/day for 2 days) of OVX rats decreased AT1R mRNA in hypothalamic-thalamic-septal tissue blocks and decreased 125I-ANG II binding to the SFO but not the PVN, MnPO, and OVLT (14). In contrast, we report changes in the SFO, as well as the MnPO and PVN; this discrepancy could be due to the difference in duration of treatment (2 days vs. 5 wk). In OVX rats treated with EB (10 µg/day for 2 days), SFO neurons exhibit decreased responsiveness to ANG II (27). Similarly, the responsiveness of anteroventral third ventricle neurons to ANG II is decreased in OVX rats treated with E2 (
125 µg/day for 10–14 days) (1). In vitro, isolated area postrema neurons treated with 100 nM (high) E2 exhibit a 24% reduction in the magnitude of ANG II-induced Ca2+ transients (21). Together, these results suggest that the OVX-induced increase and E2-induced reduction of ACE and AT1R in several angiotensinergic brain nuclei may alter the production of and responsiveness to ANG II and thereby alter the regulation of, for example, sympathetic tone, thirst, and vasopressin secretion.
Kidney
OVX increased ACE by 40–75% in the kidney at both 2 and 5 wk post-OVX. Regular E2 treatment prevented these increases, and high E2 reversed only ACE activity to a decrease at 2 wk post-OVX. Consistent with this finding, treatment of OVX rats with high E2 for 3 wk resulted in a 30% reduction in kidney ACE mRNA and activity (6). At 5 wk post-OVX, AT1R density was increased in the kidney, medulla, and cortex. Both effects were prevented by regular E2 and reversed to decreases by high E2. Similarly, in Dahl salt-sensitive rats, OVX increased kidney AT1R protein levels, an effect prevented by E2 replacement at physiological levels (9, 10).
Abdominal Aorta
OVX increased ACE activity in the abdominal aorta at 5 wk post-OVX. This increase was prevented by regular E2 and not decreased further by high E2. Tanaka et al. (28) reported that aortic ACE activity was increased post-OVX, and this increase was prevented by regular E2 treatment. High E2 treatment of OVX rats also decreased ACE activity (6). In contrast to the effects on ACE activity, OVX did not increase ACE density in the abdominal aorta, whereas high E2 treatment decreased ACE density by 26%. These discrepancies in the changes in ACE may be attributed to the technical differences in the ACE activity and autoradiography assays. Autoradiography measures ACE density at the plasma membrane only, whereas the ACE activity assay measures ACE in all subcellular fractions. E2 deficiency/excess may regulate ACE in separate fractions differently, resulting in differences in measured amounts of ACE by the two methods.
At 5 wk post-OVX, AT1R density was increased in the abdominal aorta by 59%. Regular E2 treatment prevented this increase, and high E2 reversed the increase to a 32% decrease. Consistent with this finding, at 5 wk post-OVX, AT1R mRNA abundance and binding densities were increased by 87 and 60%, respectively, in rat aorta, and replacement of E2 at physiological levels prevented these increases (19). In cultured vascular smooth muscle cells from thoracic aorta, 1 µM E2 decreased AT1R mRNA by 46% (20). The changes in AT1R were associated with parallel changes in ANG II-induced constriction of aortic rings (21). These studies suggest that E2 deficiency and replacement may alter the sensitivity of vessels to ANG II and thereby regulate vascular tone. Consistent with this hypothesis, OVX rats treated with high E2 for 3 wk exhibited attenuated pressor responses to ANG II (4).
Adrenal
E2 status did not affect ACE activity in the whole adrenal at 2 or 5 wk. In contrast, at 5 wk post-OVX, ACE density in the adrenal medulla was increased by 66%, an effect prevented by regular E2 treatment but not further reduced by high E2 treatment. In the adrenal, ACE is expressed primarily in the medulla, and measurement of ACE activity in the whole organ likely reduced the ability to detect changes in activity due to E2 status. No other studies have assessed the effects of E2 on ACE in the adrenal medulla. At 5 wk post-OVX, AT1R densities in the adrenal medulla and cortex were increased by 92 and 15%, respectively. These changes were prevented by regular E2 and reversed to decreases by high E2. In the adrenal cortex, OVX increases and E2 treatment prevents the increases in AT1R protein levels (10, 23). These effects are associated with parallel changes in ANG II-induced secretion of aldosterone (23, 33). Our data are consistent with the notion that adrenal catecholamine and/or aldosterone release may be altered by E2 status.
Plasma
OVX alone did not affect plasma ACE activity, but both regular and high E2 treatment of OVX rats transiently (after 2 but not 5 wk) reduced plasma ACE activity compared with sham OVX and OVX plus vehicle rats. Furthermore, treatment of OVX rats with regular or high E2 for 3 wk resulted in a 30% decrease in plasma ACE activity (4, 6). In contrast, at 14 wk post-OVX, serum ACE activity was increased by 45%, an effect prevented by treatment with E2 (0.2 µg/day) (28). This discrepancy may reflect a change in regulation over time. The short-term effect of OVX alone suggests that the effect on plasma ACE activity is not simply mediated by circulating levels of E2, and factors surrounding the removal of the ovaries (e.g., removal of progesterone) may be involved.
Lung
Plasma ACE is exclusively derived from its regulated cleavage-secretion from the vascular (mostly pulmonary) endothelium. At 2 wk post-OVX, the effects of E2 status on lung ACE activity are largely opposite to those occurring in plasma: a decrease due to OVX, prevention by regular E2, and reversal to increases by high E2. The decrease in plasma ACE by E2 at 2 wk post-OVX may occur via inhibition of its basal cleavage-secretion from the lung or other vascular endothelia. In aortic endothelial cells, casein kinase-2 inhibits the cleavage-secretion of ACE by phosphorylating its cytoplasmic domain (15). By 5 wk post-OVX, the effects of OVX/E2 replacement on lung ACE activity are reversed, and the decrease in plasma ACE is normalized. The mechanism of the change in lung ACE regulation between 2 and 5 wk requires further study. Because the components of the RAS tend to be regulated cooperatively, ACE regulation in the lung may be related to changes in AT1R and other proteins and peptides of the RAS that occur between 2 and 5 wk post-OVX. These changes remain to be characterized.
Several groups have studied the potential mechanisms of regulation of ACE and AT1R by E2. Incubation of E2 with purified ACE in vitro does not result in inhibition of ACE activity (7), indicating no regulation by direct interaction with the enzyme. Many actions of E2 require estrogen receptors (ERs). In rats, the heart, kidneys, adrenals, lung, blood vessels, and the OVLT, SFO, PVN, and MnPO of the brain express either ER
and/or - (2, 8, 16, 25). The E2-ER complex can regulate gene transcription rates. Although the promoter regions of the ACE and AT1R genes do not contain a consensus or near-consensus estrogen response element, both contain near-consensus activating protein-1 sites (11, 24), which could potentially be regulated by E2-ER complexes. Regulation of mRNA transcript stability and translation into protein are also possible. Treatment of cultured aortic vascular smooth muscle cells with 1 µM (high) E2 did not affect the rate of transcription of AT1R mRNA but decreased AT1R mRNA levels by shortening the half-life of the transcript from 5 to 2 h (20). Treatment of adrenal cortical cells with E2 for 8 days did not alter AT1R mRNA levels but decreased AT1R binding densities. E2 treatment increased the association of cytosolic RNA binding proteins to the 5' leader sequence of AT1R mRNA. These binding proteins interfere with ribosomal scanning and, thereby, may inhibit AT1R translation efficiency (33).
Perspectives
Similar to rats, women exhibit lower circulating E2 levels after menopause or surgical ovariectomy. Although it remains to be determined whether components of tissue RAS are negatively regulated by E2 in humans, this study identifies a potential benefit of premenopausal endogenous estrogens and postmenopausal E2 replacement therapy: a reduction in tissue ACE and AT1R. This reduction may be especially important in the presence of pathology where activation of local tissue RAS plays an etiological role such as hypertension, diabetic nephropathy, atherosclerosis, and LV remodeling post-myocardial infarction. Indeed, in Dahl salt-sensitive rats, OVX exacerbates the degree of hypertension induced by high-salt diet or aging, effects prevented by E2 replacement at physiological levels (9, 10).
In conclusion, this study demonstrates that OVX upregulates and E2 replacement reduces ACE and AT1R in several tissues of female rats, and it supports the notion that E2 may regulate the local tissue concentration of angiotensin and/or bradykinin peptides and lead to altered cardiovascular function.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
* S. A. Dean and J. Tan contributed equally to this study. 
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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-estradiol inhibits angiotensin II activation of area postrema neurons. Am J Physiol Heart Circ Physiol 285: H1515–H1520, 2003.This article has been cited by other articles:
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R. A. Khalil Sex Hormones as Potential Modulators of Vascular Function in Hypertension Hypertension, August 1, 2005; 46(2): 249 - 254. [Abstract] [Full Text] [PDF]
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