Elsevier

Maturitas

Volume 61, Issue 4, 20 December 2008, Pages 310-316
Maturitas

2-Methoxyestradiol attenuates hypertension and coronary vascular remodeling in spontaneously hypertensive rats

https://doi.org/10.1016/j.maturitas.2008.09.028Get rights and content

Abstract

Objectives

Accumulating data provide evidence that some metabolites of 17β-estradiol are biologically active and mediate multiple effects on the cardiovascular and renal systems. We investigated the effect of 2-methoxyestradiol (an active metabolite of estradiol with non-feminizing activity) on the development of hypertension and myocardial vascular remodeling in male and female ovarectomized SHR.

Methods

Rats were divided into five groups: intact females, ovarectomized (OVX), OVX+ 2-methoxyestradiol (2ME), control males, and male + 2ME. Systolic blood pressure was determined from 10 to 18 weeks. Structural changes in coronary vessels were quantified by an image analyzer. Immunoblotting of phosphorylated ERK1/2 and NADPH oxidase activity were performed on mesenteric arteries.

Results

Treatment with 2ME reduced the increase in systolic blood pressure in male and ovarectomized rats to values not different from those obtained in intact females. Myocardial arterioles and small arteries showed significant increases in wall-to-lumen ratio and perivascular fibrosis in male and ovarectomized rats when compared with intact females. NADPH oxidase activity was increased in mesenteric arteries from males and ovarectomized females as compared with intact females. Finally, the expression of phosphorilated ERK1/2 were significantly higher in mesenteric arteries from male and ovariectomized animals than in those from intact females. Those effects of ovarectomy and gender differences were totally or partially prevented by treatment with 2-methoxyestradiol.

Conclusions

These data demonstrate that 2-methoxyestradiol protects the vasculature from hypertension-induced myocardial arterial remodeling in male and ovarectomized SHR, and that might be in part related to decreased superoxide generation and ERK1/2 activation.

Introduction

In most Western societies, hypertension is a powerful risk factor for coronary heart disease. Hypertension is more common in men from 30 to 45 years old than in women of a similar age, suggesting gender differences in the physiological mechanisms controlling blood pressure. Hypertension is also more prevalent in postmenopausal than premenopausal women, suggesting vascular protective effects of female sex hormones [1], [2]. Hypertension is associated with several adaptations, including altered structural properties of the arterial wall in a variety of vascular beds [1]. Previous studies from our laboratory provide evidence for increased hypertension and vascular remodeling after ovarectomy of small coronary arteries and arterioles in 18-week-old SHR which were prevented by estradiol replacement therapy [3]. A role for the antiproliferative effects of estradiol on vascular smooth muscle cells (VSMCs) seems likely, because in these animals estradiol also decreased the expression of phosphorilated extra cellular signal-regulated kinase 1/2 content in mesenteric arteries.

Accumulating data provide convincing evidence that some metabolites of estradiol, the major estrogen secreted by human ovaries, are biologically active and mediate multiple effects on the cardiovascular and renal systems which are largely independent of classical estrogen receptors [4]. More specifically, catecholestradiols and methoxyestradiols induce multiple actions that protect the heart, blood vessels, and kidneys from disease. These protective effects may be mediated in part by the inhibition of the ability of vascular smooth muscle cells, cardiac fibroblasts, and glomerular mesangial cells to migrate, proliferate, and secrete extra cellular matrix proteins. In VSMCs from human aorta, Barchiesi et al. [5] reported that 2-methoxyestradiol (2ME) is a potent inhibitor of VSMC proliferation and migration and extra cellular matrix production, and that the sequential metabolism of estradiol to 2ME plays a major role in mediating the inhibitory effects of estradiol on VSMC growth [5], [6]. Therefore, this estrogen metabolite seems to be a good candidate for mediating the cardiovascular beneficial effects of female sex hormones. Furthermore, the use of estradiol analogues without estrogenic activity, such as 2ME, that exhibit cardiovascular protection, would provide powerful new weapons for fighting high cardiovascular morbidity and mortality in men and women.

In this regard, recently Tofovic et al. have demonstrated that estradiol metabolites have protective effects in vivo against angiotensin II-induced renal and cardiovascular injury; they found that in the constricted-aorta rat model, 2ME inhibits both pressure- and growth factor-induced cardiac and vascular remodeling [6], [7]. However, the mechanisms involved in the observed protective effects of estradiol metabolites are still unclear and further mechanistic studies of the cardio renal protection produced by 2ME in vivo are necessary. In particular, 2-methoxyestradiol is known to be a potent anti-oxidant [8] able to block the free radical-induced proliferation and migration of VSMCs, associated with its ability to attenuate peroxidation of acidic membrane phospholipids. Oxidation of membrane phospholipids is known to trigger cell migration and to activate cellular proliferative pathways such as ERK1/ERK2 and c-fos/c-jun oncogenes. Because activation of the MAP kinase cascade is a major pathway by which multiple external stimuli induce cellular proliferation, the inhibitory effects of 2ME on this pathway may also play a pivotal role in mediating their inhibitory effects on VSMC.

Hence, one of the goals of the present study was to test the hypothesis that 2ME can attenuate the development of hypertension and inhibit hypertension-induced vascular remodeling in male and ovarectomized SHR. Another aim of this study was to evaluate the effect of chronic treatment with 2ME on the superoxide production and the expression of key proteins responsible for VSMCs proliferation such as extracellular signal-regulated kinase ERK 1/2, implicated in vascular remodeling in hypertensive rats.

Section snippets

Methods

Male and female spontaneously hypertensive rats (SHR) aged 10 weeks were divided into five groups. Rats in both control groups were left intact and untreated (males, n = 21, and females, n = 26). In a third group, rats were ovarectomized (OVX, n = 23) under anesthesia with ketamine (30 mg/kg im) and xylazine (20 mg/kg im). In the fourth and fifth groups, ovarectomized females (n = 22), and control males (n = 22) were given 2-methoxyestradiol chronically infused (10 μg/(kg h)), from 10th to 18th weeks of age,

Results

No significant differences were observed in systolic blood pressure among the experimental groups at 10 weeks of age [0] (Fig. 1). However, as expected, from weeks 10 to 18 SBP increased in all groups. In intact females we found significant differences from 157 ± 2 mmHg at week 10 to values of 168 ± 3 and 169 ± 4 mmHg at 12 and 18 weeks, respectively (P < 0.05). However, in control males SBP progressively and significantly increased from week 12 reaching a value at week 18 of 193 ± 1 mmHg (P < 0.01).

Discussion

The major finding of this work is that treatment with 2ME (an active metabolite of 17β-estradiol) significantly attenuated the rise in arterial blood pressure in ovarectomized spontaneously hypertensive rats, as 17β-estradiol treatment did in the same model in a previous study from our laboratory [10]. In addition, we also observed a beneficial effect of 2ME on the evolution of blood pressure in male SHR after 3 weeks of treatment in ovarectomized female and 4–5 weeks in male rats. A similar

Acknowledgements

BFV 2006-06998 (Ministerio de Educacion y ciencia). PIO52737 (Fondo de investigaciones sanitarias). We thank Dr. Joaquín Martinez for his help in revising the manuscript.

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