2-Methoxyestradiol Reduces Monocyte Adhesion to Aortic Endothelial Cells in Ovariectomized Rats

Abstract

Abstract. 2-Methoxyestradiol (2-ME) is an endogenous metabolite of estradiol with no affinity for estrogen receptors. It inhibits cell proliferation, thus is a potentially useful drug to block the progression of atherosclerosis. As a first step to examining the anti-atherosclerotic effects of 2-ME, we investigated monocyte adhesion to aortic endothelial cells, which is considered a prerequisite to atherosclerosis in vivo. Eight-week-old Sprague-Dawley rats were ovariectomized then treated by slow-release pellets with placebo, 17-β-estradiol (5 µg/day), low-dose 2-ME (10 µg/day), or high-dose 2-ME (100 µg/day). After 6 weeks, enface analysis showed an increased number of monocytes adhering to endothelial cells of the thoracic aorta in ovariectomized rats compared with sham-operated controls. This increase was predominantly inhibited by treatment with 17β-estradiol, and low-dose or high-dose 2-ME. The observed effects were unrelated to changes in serum lipids, blood glucose, or blood pressure. Our data suggested that 2-ME mediates the anti-atherosclerotic actions of estradiol at least in part by preventing monocyte adhesion to the aortic endothelium. CARDIOVASCULAR disease is a major cause of morbidity and mortality in modern societies. In women, menopause increases the risk of cardiovascular disease [1, 2], probably due to reduced estrogen levels [3][4][5]. Hormone replacement therapy is reported to delay the onset of cardiovascular disease in postmenopausal women [6,7]. In contrast, two major randomized prospective clinical trials, the Heart and Estrogen/progestin Replacement Study (HERS) [8] and the Women's Health Initiative Study (WHI) [9], found that hormone replacement therapy increased the risk of cardiovascular disease following menopause. This discrepancy might reflect differences in study conditions. The efficacy of hormone replacement therapy to protect against atherosclerosis seems dependent on the atherosclerotic state, type of estrogen used, and the coadministration of progestin [10]. Research into the anti-atherosclerotic effect of estrogen is thus needed to establish a better method to deliver estrogen to postmenopausal women. The endogenous estrogen 17β-estradiol (E 2 ) binds to both estrogen receptor (ER) α and β. Activation of ERα and β has been linked with some, but not all, antiatherosclerotic effects of estrogen [11][12][13]. 2-methoxyestradiol (2ME), a metabolite of estradiol with no affinity for estrogen receptors, is a potent inhibitor of cell proliferation, tumor growth, and angiogenesis, and might, at least in part, mediate anti-atherosclerotic effects of estrogen [14][15][16][17]. Abbreviations: E 2 : 17β-estradiol, ER: estrogen receptor, FFA: free fatty acid, 2-ME: 2-methoxyestradiol, NEMOes: New enface method for optimal observation of endothelial surface, TC: total cholesterol, TG: triglyceride.

Antiangiogenic Therapy Inhibits Venous Thrombus Resolution

“…2ME could have also affected thrombus organization and resolution by inhibiting monocyte adhesion and subsequent infiltration. 45,46 Monocyte infiltration may be mediated by the monocyte chemoattractants VEGF and PlGF under the regulation of HIF1α. 47,48 The lack of any extra impairment of thrombus resolution by 2ME over that caused by axitinib was somewhat unexpected and suggests that a significant proportion of the observed changes seen after these treatments may be the result of inhibition of the interaction between VEGF and its receptors.…”

Synergistic Therapeutic Effects of 2-Methoxyestradiol With Either Sildenafil or Bosentan on Amelioration of Monocrotaline-induced Pulmonary Hypertension and Vascular Remodeling

“…Therefore, it is not surprising that in this study, 2ME attenuated development of PAH because 2ME exhibits both in vitro and in vivo strong antimitogenic effects in various vascular cells and has multifaceted vasoprotective and antiinflammatory effects. [4][5][6][7][8][9][10][11][12][26][27][28][29][30][31][32][33] In this regard, 2ME has antimitogenic effects in human cell lines involved in vascular remodeling in PAH. Our most recent studies report the effect of E2 and 2ME on proliferation of human pulmonary artery endothelial cells (hPAECs) and smooth muscle cells and human lung fibroblasts.…”

Modulation of adjuvant arthritis in the rat by 2-methoxyestradiol: An effect independent of an anti-angiogenic action

“…In other forms of chronic inflammation, such as in models of atherosclerosis, diabetesrelated or drug-induced glomerular and interstitial nephritis, as well as in pulmonary hypertension, 2ME2 has been recently shown to have vascular protective and antiinflammatory effects [26][27][28][29][30]. These benefits are associated with decreased monocyte adhesion to the vasculature and decrease in macrophage infiltration.…”