Methoxyestradiols Mediate the Antimitogenic Effects of Estradiol on Vascular Smooth Muscle Cells via Estrogen Receptor-Independent Mechanisms

Dubey, Raghvendra K.; Gillespie, Delbert G.; Zacharia, Lefteris C.; Rosselli, Marinella; Korzekwa, Kenneth R.; Fingerle, Juergen; Jackson, Edwin K.

doi:10.1006/bbrc.2000.3755

Cited by 77 publications

(112 citation statements)

References 18 publications

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“…Previously, using pharmacological agents to block or induce the conversion of estradiol to hydroxyestradiols and methoxyestradiols, we provided indirect evidence that methoxyestradiols mediate the vascular antimitogenic effects of estradiol. 5,13 We found similar evidence for this hypothesis in cardiac fibroblasts 14 and glomerular mesangial cells. 15 Although use of pharmacological agents provides evidence supporting our hypothesis, direct evidence for the role of methoxyestradiols as mediators of the ER-independent antimitogenic actions of estradiol is lacking.…”

supporting

confidence: 82%

“…13 These findings provide additional evidence that methoxyestradiols mediate the antimitogenic effects of estradiol in SMCs. Because this mechanism mediates the antimitogenic effects of estradiol in SMCs from both humans 8 and rats, 5 as well as in rat cardiac fibroblasts 14 and rat and human glomerular mesangial cells, 15 we conclude that this mechanism is well integrated in regulating the biological effects of estradiol in various species/organs.…”

Section: Discussionmentioning

confidence: 81%

“…13 We have demonstrated that ICI182,780 blocks the vascular antimitogenic effects of estradiol only at concentrations that inhibit the metabolism of estradiol to hydroxyestradiols. 5,13 The above findings suggest that the antiproliferative actions of estradiol are ER-independent. Because estradiol is sequentially metabolized to hydroxyestradiols by CYP450s and hydroxyestradiols are methylated to methoxyestradiols by COMT, we hypothesize that methoxyestradiols mediate the antiproliferative actions of estradiol on SMCs via ER-independent mechanisms.…”

Section: Discussionmentioning

confidence: 87%

“…In WT SMCs, the inhibitory effects of estradiol are significantly enhanced by phenobarbital, a CYP450 inducer, 13 and blocked by 1-aminobenzotriazole, a CYP450 inhibitor. 5,13 Moreover, the inhibitory effects of estradiol and 2-hydroxyestradiol are abolished by OR-486 (a COMT inhibitor). 13 These findings provide additional evidence that methoxyestradiols mediate the antimitogenic effects of estradiol in SMCs.…”

Section: Discussionmentioning

confidence: 99%

“…Using pharmacological agents, previous studies demonstrate that metabolism of estradiol to hydroxyestradiols by CYP450 followed by methylation of hydroxyestradiols by catechol-O-methyltransferase (COMT) to form methoxyestradiols is critical for estradiol-induced inhibition of SMC growth. 5 In the present study, we use aortic SMCs from COMT-knockout (COMT-KO) mice 6 that express ERs but lack methylation capability to test our hypothesis that the vascular antimitogenic effects of estradiol are mediated via an ER-independent mechanism involving formation of methoxyestradiols.…”

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confidence: 99%

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Methoxyestradiols Mediate the Antimitogenic Effects of 17β-Estradiol

et al. 2003

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Background-Studies using pharmacological agents suggest but do not prove that the antimitogenic effects of estradiol are caused by conversion of estradiol to hydroxyestradiols (mediated by CYP450s) followed by methylation of hydroxyestradiols to methoxyestradiols (mediated by catechol-O-methyltransferase, COMT). Methods and Results-To test this hypothesis more rigorously, we used aortic smooth muscle cells (SMCs) from mice lacking COMT (COMT-KO). Wild-type (WT) but not COMT-KO SMCs efficiently converted 2-hydroxyestradiol to 2-methoxyestradiol. Both WT and COMT-KO SMCs expressed estrogen receptors. Estradiol and 2-hydroxyestradiol concentration-dependently inhibited serum-induced DNA synthesis, cell numbers, and collagen synthesis in WT but not COMT-KO SMCs. 2-Methoxyestradiol inhibited DNA synthesis, cell numbers, and collagen synthesis in both WT and COMT-KO SMCs. Conclusions-These data provide strong evidence that the vascular antimitogenic effects of estradiol are estrogen receptor-independent and involve the sequential conversion of estradiol to hydroxyestradiols and then to methoxyestradiols. (Circulation. 2003;108:2974-2978.)Key Words: coronary disease Ⅲ hormones Ⅲ metabolism Ⅲ muscle, smooth Ⅲ receptors S eventeen ␤-estradiol (estradiol) inhibits the growth of vascular smooth muscle cells (SMCs), even in mice lacking estrogen receptors (ERs). 1-3 Because methoxyestradiols (major endogenous metabolites of estradiol with no affinity for ERs) inhibit growth of cancer cells, 4 it is feasible that the vascular antimitogenic effects of estradiol are mediated by methoxyestradiols. Using pharmacological agents, previous studies demonstrate that metabolism of estradiol to hydroxyestradiols by CYP450 followed by methylation of hydroxyestradiols by catechol-O-methyltransferase (COMT) to form methoxyestradiols is critical for estradiol-induced inhibition of SMC growth. 5 In the present study, we use aortic SMCs from COMT-knockout (COMT-KO) mice 6 that express ERs but lack methylation capability to test our hypothesis that the vascular antimitogenic effects of estradiol are mediated via an ER-independent mechanism involving formation of methoxyestradiols. MethodsCOMT-KO mice were developed by Dr Karayiorgou. 6 Aortic SMCs were cultured from male mice by the explant technique. SMC purity was tested by immunostaining with SMC-specific antibodies as described previously. 7 Cells in passage 2 were used.3 H]proline incorporation, and cell proliferation were conducted as previously. 7 The absence of COMT was confirmed by incubating SMCs from wild-type (WT) and COMT-KO mice for 2 hours with 2-hydroxyestradiol (2 mol/L) and analyzing 2-hydroxyestradiol/2-methoxyestradiol by high-performance liquid chromatography, as previously. 8 ER␣ and ER␤ expression were analyzed by Western blots. 9 Experiments were conducted in triplicate (repeated 3 or 4 times). Results are expressed as meanϮSEM. Statistical analyses were performed with ANOVA and Fisher's least significant difference test. A value of PϽ0.05 was considered statistically ...

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supporting

confidence: 82%

Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Methoxyestradiols Mediate the Antimitogenic Effects of 17β-Estradiol

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Sex Steroid Hormones

Regitz‐Zagrosek

Becher

Mahmoodzadeh

et al. 2008

Cardiovascular Hormone Systems

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Sex, Gender, and Sex Hormones in Pulmonary Hypertension and Right Ventricular Failure

Hester

Ventetuolo

Lahm

2019

Comprehensive Physiology

118

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Pulmonary hypertension (PH) encompasses a syndrome of diseases that are characterized by elevated pulmonary artery pressure and pulmonary vascular remodeling and that frequently lead to right ventricular (RV) failure and death. Several types of PH exhibit sexually dimorphic features in disease penetrance, presentation, and progression. Most sexually dimorphic features in PH have been described in pulmonary arterial hypertension (PAH), a devastating and progressive pulmonary vasculopathy with a 3-year survival rate <60%. While patient registries show that women are more susceptible to development of PAH, female PAH patients display better RV function and increased survival compared to their male counterparts, a phenomenon referred to as the "estrogen paradox" or "estrogen puzzle" of PAH. Recent advances in the field have demonstrated that multiple sex hormones, receptors, and metabolites play a role in the estrogen puzzle and that the effects of hormone signaling may be time and compartment specific. While the underlying physiological mechanisms are complex, unraveling the estrogen puzzle may reveal novel therapeutic strategies to treat and reverse the effects of PAH/PH. In this article, we (i) review PH classification and pathophysiology; (ii) discuss sex/gender differences observed in patients and animal models; (iii) review sex hormone synthesis and metabolism; (iv) review in detail the scientific literature of sex hormone signaling in PAH/PH, particularly estrogen-, testosterone-, progesterone-, and dehydroepiandrosterone (DHEA)-mediated effects in the pulmonary vasculature and RV; (v) discuss hormone-independent variables contributing to sexually dimorphic disease presentation; and (vi) identify knowledge gaps and pathways forward.

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Methoxyestradiols Mediate the Antimitogenic Effects of Estradiol on Vascular Smooth Muscle Cells via Estrogen Receptor-Independent Mechanisms

Cited by 77 publications

References 18 publications

Methoxyestradiols Mediate the Antimitogenic Effects of 17β-Estradiol

Methoxyestradiols Mediate the Antimitogenic Effects of 17β-Estradiol

Sex Steroid Hormones

Sex, Gender, and Sex Hormones in Pulmonary Hypertension and Right Ventricular Failure

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