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Vascular Biology

Estrogen Effects on Vascular Inflammation Are Age Dependent

Role of Estrogen Receptors

Meaghan R. Bowling, Dongqi Xing, Akash Kapadia, Yiu-Fai Chen, Alexander J. Szalai, Suzanne Oparil, Fadi G. Hage
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https://doi.org/10.1161/ATVBAHA.114.303629
Arteriosclerosis, Thrombosis, and Vascular Biology. 2014;ATVBAHA.114.303629
Originally published May 29, 2014
Meaghan R. Bowling
From Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility (M.R.B.), Vascular Biology and Hypertension Program, Division of Cardiovascular Disease (D.X., Y.-F.C., S.O., F.G.H.), Division of Clinical Immunology and Rheumatology (A.J.S.), Department of Medicine, and the School of Medicine (A.K.), University of Alabama at Birmingham; and Section of Cardiology, Birmingham Veteran’s Administration Medical Center, AL (F.G.H.).
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Dongqi Xing
From Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility (M.R.B.), Vascular Biology and Hypertension Program, Division of Cardiovascular Disease (D.X., Y.-F.C., S.O., F.G.H.), Division of Clinical Immunology and Rheumatology (A.J.S.), Department of Medicine, and the School of Medicine (A.K.), University of Alabama at Birmingham; and Section of Cardiology, Birmingham Veteran’s Administration Medical Center, AL (F.G.H.).
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Akash Kapadia
From Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility (M.R.B.), Vascular Biology and Hypertension Program, Division of Cardiovascular Disease (D.X., Y.-F.C., S.O., F.G.H.), Division of Clinical Immunology and Rheumatology (A.J.S.), Department of Medicine, and the School of Medicine (A.K.), University of Alabama at Birmingham; and Section of Cardiology, Birmingham Veteran’s Administration Medical Center, AL (F.G.H.).
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Yiu-Fai Chen
From Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility (M.R.B.), Vascular Biology and Hypertension Program, Division of Cardiovascular Disease (D.X., Y.-F.C., S.O., F.G.H.), Division of Clinical Immunology and Rheumatology (A.J.S.), Department of Medicine, and the School of Medicine (A.K.), University of Alabama at Birmingham; and Section of Cardiology, Birmingham Veteran’s Administration Medical Center, AL (F.G.H.).
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Alexander J. Szalai
From Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility (M.R.B.), Vascular Biology and Hypertension Program, Division of Cardiovascular Disease (D.X., Y.-F.C., S.O., F.G.H.), Division of Clinical Immunology and Rheumatology (A.J.S.), Department of Medicine, and the School of Medicine (A.K.), University of Alabama at Birmingham; and Section of Cardiology, Birmingham Veteran’s Administration Medical Center, AL (F.G.H.).
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Suzanne Oparil
From Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility (M.R.B.), Vascular Biology and Hypertension Program, Division of Cardiovascular Disease (D.X., Y.-F.C., S.O., F.G.H.), Division of Clinical Immunology and Rheumatology (A.J.S.), Department of Medicine, and the School of Medicine (A.K.), University of Alabama at Birmingham; and Section of Cardiology, Birmingham Veteran’s Administration Medical Center, AL (F.G.H.).
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Fadi G. Hage
From Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility (M.R.B.), Vascular Biology and Hypertension Program, Division of Cardiovascular Disease (D.X., Y.-F.C., S.O., F.G.H.), Division of Clinical Immunology and Rheumatology (A.J.S.), Department of Medicine, and the School of Medicine (A.K.), University of Alabama at Birmingham; and Section of Cardiology, Birmingham Veteran’s Administration Medical Center, AL (F.G.H.).
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Abstract

Objective—17β-Estradiol (E2) offers cardiovascular protection in young female animals and postmenopausal women. In contrast, randomized trials of menopausal hormones performed in older women have shown harm or no cardiovascular benefit. We hypothesize that E2 effects on vascular inflammation are age dependent.

Approach and Results—Young (10 weeks) and aged (52 weeks) female C57BL/6 mice were used as source for primary cultures of bone marrow–derived macrophages (BMMs) and vascular smooth muscle cells (VSMCs). E2 pretreatment of cells derived from young mice attenuated C-reactive protein (CRP)–induced expression of inflammatory mediators. In contrast, E2 pretreatment of cells from aged mice did not alter (BMMs) or paradoxically exaggerated (VSMCs) inflammatory mediator response to CRP. Using E2 receptor (ER) knockout mice, we demonstrated that E2 regulates inflammatory response to CRP in BMMs via ERα and in VSMCs via ERβ. BMMs derived from aged (versus young) mice expressed significantly less ERα mRNA and protein. A selective ligand of the novel ER GPR30 reproduced the E2 effects in BMMs and VSMCs. Unlike in young mice, E2 did not reduce neointima formation in ligated carotid arteries of aged CRP transgenic mice.

Conclusions—E2 attenuates inflammatory response to CRP in BMMs and VSMCs derived from young but not aged mice and reduces neointima formation in injured carotid arteries of young but not aged CRP transgenic mice. ERα expression in BMMs is greatly diminished with aging. These data suggest that vasoprotective effects of E2 are age dependent and may explain the vasotoxic effects of E2 seen in clinical trials of postmenopausal women.

  • aging
  • c-reactive protein
  • estrogen
  • vascular system injuries
  • Received January 8, 2013.
  • Accepted April 21, 2014.
  • © 2014 American Heart Association, Inc.
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    Estrogen Effects on Vascular Inflammation Are Age Dependent
    Meaghan R. Bowling, Dongqi Xing, Akash Kapadia, Yiu-Fai Chen, Alexander J. Szalai, Suzanne Oparil and Fadi G. Hage
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2014;ATVBAHA.114.303629, originally published May 29, 2014
    https://doi.org/10.1161/ATVBAHA.114.303629

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    Estrogen Effects on Vascular Inflammation Are Age Dependent
    Meaghan R. Bowling, Dongqi Xing, Akash Kapadia, Yiu-Fai Chen, Alexander J. Szalai, Suzanne Oparil and Fadi G. Hage
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2014;ATVBAHA.114.303629, originally published May 29, 2014
    https://doi.org/10.1161/ATVBAHA.114.303629
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