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Endocrinology Vol. 148, No. 9 4128-4132
Copyright © 2007 by The Endocrine Society

BRIEF COMMUNICATION

The Endogenous Estradiol Metabolite 2-Methoxyestradiol Reduces Atherosclerotic Lesion Formation in Female Apolipoprotein E-Deficient Mice

Johan Bourghardt, Göran Bergström, Alexandra Krettek, Sara Sjöberg, Jan Borén and Åsa Tivesten

The Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at Göteborg University, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden

Address all correspondence and requests for reprints to: Åsa Tivesten, Wallenberg Laboratory for Cardiovascular Research, Bruna Stråket 16, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail: asa.tivesten{at}medic.gu.se.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Estradiol, the major endogenous estrogen, reduces experimental atherosclerosis and metabolizes to 2-methoxyestradiol in vascular cells. Currently undergoing evaluation in clinical cancer trials, 2-methoxyestradiol potently inhibits cell proliferation independently of the classical estrogen receptors. This study examined whether 2-methoxyestradiol affects atherosclerosis development in female mice. Apolipoprotein E-deficient mice, a well-established mouse model of atherosclerosis, were ovariectomized and treated through slow-release pellets with placebo, 17ß-estradiol (6 µg/d), or 2-methoxyestradiol [6.66 µg/d (low-dose) or 66.6 µg/d (high-dose)]. After 90 d, body weight gain decreased and uterine weight increased in the high-dose but not low-dose 2-methoxyestradiol group. En face analysis showed that the fractional area of the aorta covered by atherosclerotic lesions decreased in the high-dose 2-methoxyestradiol (52%) but not in the low-dose 2-methoxyestradiol group. Total serum cholesterol levels decreased in the high- and low-dose 2-methoxyestradiol groups (19%, P < 0.05 and 21%, P = 0.062, respectively). Estradiol treatment reduced the fractional atherosclerotic lesion area (85%) and decreased cholesterol levels (42%). In conclusion, our study shows for the first time that 2-methoxyestradiol reduces atherosclerotic lesion formation in vivo. The antiatherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity may argue that trials on cardiovascular effects of hormone replacement therapy should use estradiol rather than other estrogens. Future research should define the role of 2-methoxyestradiol as a mediator of the antiatherosclerotic actions of estradiol. Furthermore, evaluation of the effects of 2-methoxyestradiol on cardiovascular disease endpoints in ongoing clinical trials is of great interest.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE MALE PREPONDERANCE in cardiovascular disease often has been ascribed to the protective effects of endogenous estrogens in premenopausal women (1, 2). Numerous studies reporting beneficial effects of estradiol, the major endogenous estrogen, on serum lipids, vascular endothelial function, and experimental atherosclerosis support this assumption (1). Recent results from the Women’s Health Initiative showed that hormone replacement therapy may increase the risk for myocardial infarction and ischemic stroke in postmenopausal women, thus challenging the "estrogen protection hypothesis" (3, 4). The mechanisms underlying these results remain undetermined, raising skepticism about whether the correct estrogen compound was used (5, 6).

Sex steroids are synthesized and metabolized locally in peripheral target tissues, and some sex steroid metabolites are biologically active (7). Hydroxylation and subsequent methylation to methoxyestradiols provide an important pathway for the metabolism of estradiol (7). Enzymes necessary for the metabolism of estradiol to methoxyestradiols, e.g. 2-methoxyestradiol, are expressed in vascular cells (8). Furthermore, 2-methoxyestradiol circulates at measurable levels in humans (7).

During the past decade, much interest has focused on 2-methoxyestradiol, a potent inhibitor of cell proliferation, tumor growth, and angiogenesis currently being evaluated in multiple tumor types in phase II clinical trials (9). Although the mechanism of action of 2-methoxyestradiol requires additional clarification, it appears to be independent of the classical estrogen receptors (9, 10).

2-Methoxyestradiol inhibits the proliferation of vascular smooth muscle cells and inhibits injury-induced neointima formation in vivo (11). Moreover, 2-methoxyestradiol has vasculoprotective effects in rat models of drug-induced hypertension and pulmonary hypertension (12, 13) and reduces the oxidation of low-density lipoprotein in vitro (14), raising the question of whether 2-methoxyestradiol might have antiatherosclerotic effects. Hypotheses that 2-methoxyestradiol can modulate atherogenesis (10) currently remain untested in vivo.

To examine whether 2-methoxyestradiol affects atherosclerosis development in female mice, we treated apolipoprotein E-deficient (ApoE–/–) mice, a well-established mouse model of atherosclerosis, with 2-methoxyestradiol and quantified atherosclerotic lesion area in the aorta.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and study protocol
Female ApoE–/– mice (Taconic Europe, Lille Skensved, Denmark) housed in a temperature- and humidity-controlled room with a 0600–1800 h light cycle consumed a soy-free diet (2016; Harlan Teklad, Oxfordshire, UK) and tap water ad libitum. All procedures were approved by the Ethics Committee on Animal Care and Use in Göteborg and conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals (7th edition, 1996).

At 4–5 wk of age (mean weight, 14.8 g), mice anesthetized with isoflurane (Baxter Medical AB, Kista, Sweden) were either sham operated or bilaterally ovariectomized and then implanted subcutaneously with small pellets (Innovative Research of America, Sarasota, FL) that slowly released 17ß-estradiol or 2-methoxyestradiol (Sigma, St. Louis, MO) for 90 d. The animals were divided randomly into five groups: sham-operation + placebo (Sham; n = 11); ovariectomy + placebo (P; n = 11); ovariectomy + 17ß-estradiol (6 µg/d) (E; n = 13); ovariectomy + 2-methoxyestradiol (6.66 µg/d) (ME low; n = 12); and ovariectomy + 2-methoxyestradiol (66.6 µg/d) (ME high; n = 12). We chose an estradiol dose of 6 µg/d because several previous studies showed that it reduced atherosclerotic lesion development in ApoE–/– mice (1), and 6.66 µg 2-methoxyestradiol is equimolar to 6 µg estradiol.

After 90 d of treatment, the fasting mice were anesthetized with isoflurane, and a catheter (heat-stretched polyethylene 50) was placed into the left carotid artery for direct measurement of mean arterial pressure. We used a computerized data acquisition software program (Pharmlab 3.0; AstraZeneca, Mölndal, Sweden) to collect the data. After stabilization of the arterial pressure trace, data were averaged over a period of 2 min. Thereafter, the mice were given pentobarbital ip (Apoteksbolaget, Uppsala, Sweden), blood was drawn from the left ventricle, and the circulatory system was perfused with PBS (pH 7.4) under physiological pressure. The entire aorta was dissected out from the heart to the iliac bifurcation and fixed in 4% paraformaldehyde for subsequent en face evaluation. We examined 9–11 aortas in each group.

Quantification of atherosclerotic lesion area
The aortas were prepared and analyzed en face. In brief, the aortas were dissected free from connective and adipose tissue, cut open longitudinally, and pinned flat on silicone-coated dishes. The aortas were stained with Sudan IV for lipids, and images were captured. The outline of the aortic surface and lesions were defined manually, and lesion areas were computed by an image analysis program (BioPix Software, Göteborg, Sweden). The extent of atherosclerosis was expressed as the percentage of the aortic surface covered by lesions. Analyses were performed by a blinded observer.

Analysis of serum lipids
Total cholesterol and triglycerides in individual serum samples were analyzed with a Konelab 30 automated analyzer (Thermo Electron, Waltham, MA) using the reagents triglyceride 981786 and cholesterol 981773 as recommended by the manufacturer. The lipid distribution in serum lipoprotein fractions was assessed in pooled serum by fast-performance liquid chromatography gel filtration with a Superose 6 HR 10/30 column (Pharmacia, Uppsala, Sweden) (15).

Statistical analysis
Data are expressed as mean ± SEM. P < 0.05 was considered statistically significant. Statistical analysis was performed with the nonparametric Kruskal-Wallis test (all groups), followed by post hoc testing using Mann-Whitney U test (comparison of P vs. Sham, E, ME low, and ME high, respectively).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effects of 2-methoxyestradiol on body and organ weight
To examine the effect of the chosen doses of 2-methoxyestradiol on estrogen target organs, we collected uterus and thymus weights at the end of our study as well as body weight gain during the treatment period. After 90 d of treatment, high- but not low-dose 2-methoxyestradiol reduced body weight gain compared with placebo (Table 1Go). Low-dose 2-methoxyestradiol did not affect uterine weight, whereas high-dose 2-methoxyestradiol increased such weight. Uterine weight in estradiol-treated ovariectomized mice exceeded that of sham controls. High-dose 2-methoxyestradiol increased thymus weight slightly, and estradiol decreased thymus weight substantially.


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  		TABLE 1. Body weight gain and organ weight

 
Effects of 2-methoxyestradiol on atherosclerosis
To examine the effect of 2-methoxyestradiol on atherosclerosis, we evaluated the aortic atherosclerotic lesions en face. High-dose 2-methoxyestradiol reduced the fractional area of the aorta covered by discernible atherosclerotic lesions (52%) compared with placebo (Fig. 1Go), and low-dose 2-methoxyestradiol showed no effect vs. placebo. Estradiol reduced fractional lesion area (85%).


Figure 1
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  		FIG. 1. Female ApoE–/– mice were ovariectomized and treated with placebo (P), 17ß-estradiol (6 µg/d) (E), or 2-methoxyestradiol [6.66 µg/d (ME low) or 66.6 µg/d (ME high)] for 90 d. Sham-operated, placebo-treated mice were also included (Sham). n = 9–11. Data are mean ± SEM. *, P < 0.05; **, P < 0.001 vs. placebo (Kruskal-Wallis followed by Mann-Whitney U test).

 
Detailed analysis showed that high-dose 2-methoxyestradiol reduced the number of lesions in the aorta (33%) compared with placebo (Table 2Go). We also observed a nonsignificant tendency toward smaller lesion size in the high-dose 2-methoxyestradiol group. Low-dose 2-methoxyestradiol affected neither lesion number nor size. Estradiol treatment completely abolished atherosclerosis development in six of 11 aortas examined. Ovariectomy per se did not affect atherosclerotic lesion area.


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  		TABLE 2. Characteristics of atherosclerotic lesions

 
Effects of 2-methoxyestradiol on serum lipids and blood pressure
To search for possible mechanisms that mediate the effect of 2-methoxyestradiol on atherosclerosis, we assessed serum lipids and blood pressure at the end of our study. High-dose 2-methoxyestradiol reduced serum total cholesterol levels (19%) compared with placebo (Table 3Go), as did low-dose 2-methoxyestradiol (21% vs. placebo; P = 0.062) and estradiol (42%). Superose 6 chromatography of pooled serum showed similar lipid distribution in lipoprotein fractions among groups; cholesterol reduction by 2-methoxyestradiol and estradiol was reflected mainly in the atherogenic intermediate-density lipoprotein and very-low-density lipoprotein fractions (data not shown). Serum triglycerides levels were reduced by estradiol but not by high- or low-dose 2-methoxyestradiol (Table 3Go). The cholesterol/triglyceride ratio did not differ between groups in the very-low-density/intermediate-density or high-density lipoproteins (Table 3Go). Thus, estradiol or 2-methoxyestradiol treatment did not alter the size or composition of lipoprotein particles. Finally, estradiol reduced mean arterial blood pressure compared with placebo, whereas 2-methoxyestradiol treatment did not affect blood pressure (Table 3Go).


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  		TABLE 3. Serum lipids and mean arterial blood pressure

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Possible effects of estradiol metabolites on atherogenesis have not been studied previously in vivo. Our study shows for the first time that 2-methoxyestradiol, an estradiol metabolite, reduces atherosclerotic lesion formation in female ApoE–/– mice, in conjunction with a small reduction of total cholesterol levels.

Our findings are in accordance with previous studies showing that 2-methoxyestradiol inhibits injury-induced neointima formation in vivo (11) and exerts vasculoprotective effects in rat models of drug-induced hypertension and pulmonary hypertension (12, 13, 16). Importantly, besides a study in pulmonary hypertension (16), these previous studies were performed in male animals. Our study supports that 2-methoxyestradiol may exert protective effects in both males and females.

Our findings raise the possibility that 2-methoxyestradiol may partially mediate the antiatherosclerotic effect of estradiol in mouse models of atherosclerosis, a notion supported by the fact that estradiol exerts antiatherosclerotic effects in estrogen receptor {alpha} knockout mice (17). Thus, given that 2-methoxyestradiol may be unable to engage estrogen receptors as an agonist (18, 19) and that estradiol is fully protective in the absence of estrogen receptor ß (1), it is possible that the antiatherosclerotic effects of estradiol in estrogen receptor {alpha} knockout mice are mediated by 2-methoxyestradiol. Interestingly, sequential metabolism of estradiol to methoxyestradiols participates critically in the antiproliferative effects of estradiol on vascular smooth muscle cells (20). Specific determination of the role of this metabolism for the antiatherogenic effects of estradiol will require additional study of estradiol treatment in combination with blockade or knockout of the enzymes that convert estradiol to methoxyestradiols.

Although most experimental studies that showed antiatherogenic effects of estrogens used estradiol, two large clinical trials conducted on hormone replacement therapy in postmenopausal women used conjugated equine estrogens (CEEs) as the estrogen component (3, 21). These trials unexpectedly demonstrated adverse cardiovascular effects of treatment, raising skepticism about whether the correct estrogen compound was used (5, 6). CEEs contain more than 10 estrogens extracted from horse urine, and their exact composition remains undetermined. However, CEEs contain very small amounts of estradiol (6), thus generating little or no estradiol metabolites. Our present results on antiatherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity suggest that future trials should use estradiol rather than other estrogens; alternatively, such trials might evaluate the use of 2-methoxyestradiol for hormone replacement therapy. Furthermore, our data suggest that this potential anticancer drug, currently evaluated by several phase II clinical trials for cancer (9), also has promise for the prevention of cardiovascular disease.

We examined two possible mediators, serum lipids and blood pressure, for the effect of 2-methoxyestradiol on atherosclerosis in female mice. Concordant with previous observations in rats (22), 2-methoxyestradiol reduced serum total cholesterol levels in ApoE–/– mice. Although the role of such reduction in atherosclerosis remains unclear, it may be less important because it occurred in both the low-dose and high-dose 2-methoxyestradiol groups and atherosclerotic lesion area decreased only in the high-dose group. Notably, the antiatherosclerotic effects of estradiol do not require reduced levels of serum cholesterol in mouse models (1). Additionally, because 2-methoxyestradiol did not alter mean arterial blood pressure measured at the end of our study, it seems unlikely that it modulates atherogenesis through a blood pressure mechanism. Theoretically, however, several other possible mechanisms may explain the effect of 2-methoxyestradiol on atherosclerosis. For example, 2-methoxyestradiol exerts antiproliferative effects on vascular smooth muscle cells (11), reduces oxidative stress and oxidation of low-density lipoproteins in vitro (8, 14), and increases cyclooxygenase-2 expression and prostacyclin generation (11, 23), all participants in atherogenesis (10, 24, 25).

Our study supports previous observations that 2-methoxyestradiol shares the effects of estradiol on, for example, serum total cholesterol, body weight gain, and uterine weight (22). One hypothetical mechanism for these estrogenic effects involves possible demethylation of 2-methoxyestradiol to 2-hydroxyestradiol, which acts in turn as an estrogen receptor agonist (9). Another possibility is that 2-methoxyestradiol, attributable to cell-specific cofactors, can activate estrogen receptors in cell types other than, for example, breast carcinoma cells and porcine endothelial cells, in which it is unable to engage estrogen receptors as an agonist (18, 19). An interesting exception to the concordant effects of estradiol and 2-methoxyestradiol observed in this study involves thymus weight, which was decreased by estradiol but increased by 2-methoxyestradiol. Thus, 2-methoxyestradiol treatment may result in phenotypical changes that are both similar and different from those induced by estradiol. A possible explanation for this is that demethylation of 2-methoxyestradiol occurs locally in some (e.g. uterus), but not other (e.g. thymus), tissues so that the estrogenic effect is tissue specific. Clearly, the pathways for the diverse effects of 2-methoxyestradiol require additional study.

Importantly, the role of demethylation and/or activation of estrogen receptors for the atheroprotective effects of 2-methoxyestradiol in this study remains unclear. Thus, whether estradiol is effective via conversion to 2-methoxyestradiol or whether 2-methoxyestradiol is effective via conversion to estrogenic compounds, or whether both mechanisms are operative, is undefined. However, the cholesterol-lowering effect of 2-methoxyestradiol is not associated with activation of the classical estrogen receptor (7). Furthermore, the effect of 2-methoxyestradiol on vascular smooth muscle cell proliferation is a direct effect of this metabolite (20) and is not affected by estrogen receptor blockade (26). Finally, as discussed above, 2-methoxyestradiol directly exerts multiple other effects that may generate antiatherogenic action.

In the present study, the effects of 2-methoxyestradiol were not as marked as the effects of estradiol on, for example, reducing atherosclerotic lesion formation, cholesterol, and triglycerides. There are several possible explanations for this pattern, related to, for example, pharmakokinetics, that different pathways are involved or that the effect of 2-methoxyestradiol is a component of the effect of estradiol. However, proper comparison of the atheroprotective effects of estradiol and 2-methoxyestradiol will require dose-response studies. Although low-dose 2-methoxyestradiol had no effect on other study variables, low- and high-dose 2-methoxyestradiol similarly decreased total cholesterol levels, albeit not statistically significant in the low-dose group. It may be speculated that the cholesterol-lowering effect is exerted through a distinct mechanism resulting in a different dose-response relationship. This idea is supported by previous studies (22, 27).

Because technical restraints limit the ability to measure circulating or tissue levels of 2-methoxyestradiol in mice, the demarcation between physiological and pharmacological 2-methoxyestradiol treatment remains undefined. However, the dose of estradiol used in the present as well as previous atherosclerosis studies (1) is clearly supraphysiological, as determined by uterine weight. Notably, some studies have shown antiatherogenic effects of estradiol doses in the physiological range (1). In accordance with previous results (28), ovariectomy per se did not affect the atherosclerotic lesion area, possibly because ovariectomy entails loss of proatherogenic androgens as well as estrogens.

In conclusion, our study shows for the first time that 2-methoxyestradiol, an endogenous estradiol metabolite, reduces atherosclerotic lesion formation in vivo. This finding has several implications: 1) 2-methoxyestradiol may partially mediate the antiatherosclerotic effect of estradiol in mouse models; 2) the antiatherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity may argue that clinical trials on cardiovascular effects of hormone replacement therapy should use estradiol rather than other estrogens; and 3) 2-methoxyestradiol, currently undergoing evaluation in phase II trials for cancer, also may hold promise for cardiovascular disease prevention. Future research should define the role of 2-methoxyestradiol as a mediator of the antiatherosclerotic actions of estradiol. Furthermore, evaluation of the effects of 2-methoxyestradiol on cardiovascular disease endpoints in ongoing, and future clinical trials is of great interest.


   Acknowledgments
 
We thank Gunnel Andersson, Jia Jing, Elin Björk, and Anneli Carlsson for excellent assistance.


   Footnotes
 
This study was financially supported by grants from the Swedish Heart and Lung Foundation, the Novo Nordisk Foundation, the Göteborg Medical Society, the Tore Nilson Foundation, an ALF (Avtal om Läkarutbildning och Forskning) research grant in Göteborg, the Emelle Foundation, and the Swedish Medical Society.

Disclosure Statement: The authors have nothing to disclose.

First Published Online April 19, 2007

Abbreviations: ApoE, Apolipoprotein E; CEE, conjugated equine estrogen.

Received February 23, 2007.

Accepted for publication April 9, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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R. K. Dubey, B. Imthurn, and E. K. Jackson
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