Sexually Dimorphic Response of the Balloon-Injured Rat Carotid Artery to Hormone Treatment

Oparil, Suzanne; Levine, Roger; Chen, Shi-Juan; Durand, Joan; Chen, Y.F.

doi:10.1161/01.cir.95.5.1301

Cited by 87 publications

(51 citation statements)

References 32 publications

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“…An ER-independent mechanism is also supported by the observations that estradiol inhibits injury-induced neointima formation in gonadectomized but not intact male rats, although vascular cells from both express ERs. 10 Pharmacological evidence for a role of ERs in mediating the antimitogenic effects of estradiol in SMCs is controversial. ICI182,780, an ER antagonist, was effective in blocking the injury-induced neointima formation in one study 11 but not in another.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

Methoxyestradiols Mediate the Antimitogenic Effects of 17β-Estradiol

et al. 2003

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“…65 Estradiol prevents neointima formation in mice lacking functional ER␣ and ER␤, 66,67 suggesting that the protective effects of estradiol on the cardiovascular system may be ER-independent. Estradiol prevents neointima formation in gonadectomized, but not intact, male rats, 68 even though male rats express ERs. In female rats, the inhibitory effects of estradiol are abrogated by MPA.…”

Section: Type Of Estrogenmentioning

confidence: 94%

Hormone Replacement Therapy and Cardiovascular Disease

et al. 2004

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Abstract-Observational studies in humans and experimental studies in animals and isolated cells supported the widely held belief that hormone replacement therapy protects the cardiovascular system from disease. To nearly everyone's astonishment, the Women's Health Initiative Study and the Heart and Estrogen/Progestin Replacement Study overturned the conclusion that hormone replacement therapy protects the cardiovascular system and, in fact, supported the opposite view that such therapy may actually increase the risk of cardiovascular disease. Observational Studies Suggest HRT Has Beneficial Cardiovascular EffectsIn modern societies, cardiovascular disease is the main cause of morbidity and mortality in men and women. Women, however, are comparatively spared. For example, in people younger than age 65 years, the prevalence of coronary heart disease (CHD) is several-fold higher in men. 3,4 Although CHD prevalence increases with age in both genders, before the age of 65 years the relationship between age and CHD prevalence is shifted rightward by 5 years in women; 5,6 compared with postmenopausal women, CHD deaths are rare in premenopausal women. 7 Autopsy studies demonstrated increased CHD in oophorectomized young women, 8 and several studies demonstrated an increased risk of cardiovascular disease in women with bilateral oophorectomy without HRT compared with those receiving HRT. 9,10 Women with natural early-onset menopause who did not use HRT had a greater likelihood for CHD compared with age-matched premenopausal women. 9,11 Also, studies reported an inverse relationship between age at natural menopause and mortality from CHD 12,13 and carotid atherosclerosis. 14 Bush et al demonstrated that HRT was associated with reduced all-cause mortality in postmenopausal women, 15 primarily because of favorable effects on high-density lipoprotein. 16 Barrett-Connor and Bush 8 reported that many, but not all, cross-sectional and prospective studies demonstrated a statistically significant reduction in CHD in women taking HRT, and Grady et al 17 presented a meta-analysis of published observational studies and reported that HRT was associated with one-third less fatal CHD. An up-to-date meta-analysis of 25 observational studies conducted between 1976 and 1996 showed that the relative risk for CHD in women who ever used HRT compared with never users was 0.70. 18 The Nurses' Health Study was a comprehensive investigation conducted in 121 700 female nurses aged 30 to 55 years. In the latest report, compiled with data from 70 533 postmenopausal women followed-up for 20 years, the overall risk of CHD in current users of HRT was reduced, with a relative risk of 0.61 after adjustment for age and cardiovascular risk factors. 19

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“…Initially, we demonstrated a sexual dimorphism in the vascular injury response that was estrogen-dependent. [47][48][49] Neointima formation after carotid injury was greater in male rats than in female rats; orchidectomy with or without testosterone replacement did not alter the injury response in males, but ovariectomy greatly enhanced neointima formation in female rats, and testosterone administration had no additional effect. Systemic administration of 17␤-estradiol in a dose that resulted in physiological levels of circulating hormone markedly attenuated neointima formation in gonadectomized rats of both sexes (Figure 4), providing strong evidence that the sexual dimorphism of neointima formation after endoluminal vascular injury is mediated by estrogen.…”

Section: Mechanistic Studies Of Hormones and Vascular Inflammationmentioning

confidence: 98%

“…Balloon injury of the rat carotid artery has been used as an experimental model of localized and highly controllable vascular damage in which the injury response can be studied in vivo. [47][48][49] In this model, balloon inflation denudes endothelium and induces highly reproducible neointima formation over the entire length of the affected vessel. Our laboratory has used this model to show that ovarian hormones modulate the neointimal response to endoluminal vascular injury.…”

Section: Mechanistic Studies Of Hormones and Vascular Inflammationmentioning

confidence: 99%

Hormone Replacement Therapy and Inflammation

et al. 2003

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Abstract-Inflammation plays a central role in the pathogenesis of many forms of vascular disease, including atherosclerosis. Atherogenesis begins with endothelial damage, and the damaged endothelium expresses adhesion molecules, chemokines, and proinflammatory cytokines that direct atherosclerotic plaque formation and spill into the circulation as biomarkers of atherosclerotic disease risk. Menopausal hormone therapy, including a variety of estrogen preparations with or without a progestin, has negative modulatory effects on most of these soluble inflammatory markers, including E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-␣, inconsistent effects on interleukin-6, and stimulatory effects on transforming growth factor-␤, a vasoprotective cytokine. In contrast, C-reactive protein, a circulating proinflammatory cytokine produced in both liver and atherosclerotic arteries, increases in response to oral conjugated estrogens but not to transdermal estrogen. Although C-reactive protein is clearly linked to increased cardiovascular disease risk in women, the hormone-induced rise in this biomarker is not associated with increased risk and may be related to a first-pass effect of C-reactive protein production in the liver after oral estrogen absorption. Many important questions about the effects of ovarian hormones on vascular inflammation and the pathogenesis of vascular disease cannot be answered in human subjects. Insights from fundamental mechanistic studies in animal models are needed to delineate the cellular/molecular events that determine whether these hormones protect or injure blood vessels.

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Sexually Dimorphic Response of the Balloon-Injured Rat Carotid Artery to Hormone Treatment

Cited by 87 publications

References 32 publications

Methoxyestradiols Mediate the Antimitogenic Effects of 17β-Estradiol

Methoxyestradiols Mediate the Antimitogenic Effects of 17β-Estradiol

Hormone Replacement Therapy and Cardiovascular Disease

Hormone Replacement Therapy and Inflammation

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