title: Estrogen effects on vascular inflammation are age dependent: role of estrogen receptors.
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.
  
  
  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.
authors.affiliation: 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.) and the Division of Clinical Immunology and Rheumatology (A.J.S.), Department of Medicine, and the School of Medicine (A.K.), The University of Alabama at Birmingham, Birmingham, AL 35294, USA, Section of Cardiology, Birmingham Veteran's Administration Medical Center, Birmingham, AL 35294, USA (F.G.H.).
authors.forename: Meaghan R
authors.initials: MR
authors.lastname: Bowling
authors.affiliation: 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.) and the Division of Clinical Immunology and Rheumatology (A.J.S.), Department of Medicine, and the School of Medicine (A.K.), The University of Alabama at Birmingham, Birmingham, AL 35294, USA, Section of Cardiology, Birmingham Veteran's Administration Medical Center, Birmingham, AL 35294, USA (F.G.H.).
authors.forename: Dongqi
authors.initials: D
authors.lastname: Xing
authors.affiliation: 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.) and the Division of Clinical Immunology and Rheumatology (A.J.S.), Department of Medicine, and the School of Medicine (A.K.), The University of Alabama at Birmingham, Birmingham, AL 35294, USA, Section of Cardiology, Birmingham Veteran's Administration Medical Center, Birmingham, AL 35294, USA (F.G.H.).
authors.forename: Akash
authors.initials: A
authors.lastname: Kapadia
authors.affiliation: 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.) and the Division of Clinical Immunology and Rheumatology (A.J.S.), Department of Medicine, and the School of Medicine (A.K.), The University of Alabama at Birmingham, Birmingham, AL 35294, USA, Section of Cardiology, Birmingham Veteran's Administration Medical Center, Birmingham, AL 35294, USA (F.G.H.).
authors.forename: Yiu-Fai
authors.initials: YF
authors.lastname: Chen
authors.affiliation: 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.) and the Division of Clinical Immunology and Rheumatology (A.J.S.), Department of Medicine, and the School of Medicine (A.K.), The University of Alabama at Birmingham, Birmingham, AL 35294, USA, Section of Cardiology, Birmingham Veteran's Administration Medical Center, Birmingham, AL 35294, USA (F.G.H.).
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Szalai
authors.affiliation: 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.) and the Division of Clinical Immunology and Rheumatology (A.J.S.), Department of Medicine, and the School of Medicine (A.K.), The University of Alabama at Birmingham, Birmingham, AL 35294, USA, Section of Cardiology, Birmingham Veteran's Administration Medical Center, Birmingham, AL 35294, USA (F.G.H.).
authors.forename: Suzanne
authors.initials: S
authors.lastname: Oparil
authors.affiliation: 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.) and the Division of Clinical Immunology and Rheumatology (A.J.S.), Department of Medicine, and the School of Medicine (A.K.), The University of Alabama at Birmingham, Birmingham, AL 35294, USA, Section of Cardiology, Birmingham Veteran's Administration Medical Center, Birmingham, AL 35294, USA (F.G.H.).
authors.forename: Fadi G
authors.initials: FG
authors.lastname: Hage
mesh_terms: D000367:Age Factors; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism; D020212:Carotid Artery Injuries / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D058426:Neointima; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C532507:GPER1 protein, mouse; D018836:Inflammation Mediators; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D004958:Estradiol; D002097:C-Reactive Protein
keywords: aging; c-reactive protein; estrogen; vascular system injuries