Skip to main content

Advertisement

SpringerLink
Log in

Proatherogenic effects of estradiol in a model of accelerated atherosclerosis in ovariectomized ApoE-deficient mice

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Clinical studies revealed unfavorable effects of hormone replacement therapy in postmenopausal women despite strong evidence for vasoprotective effects of estrogen in animal models. Therefore, an attempt was made to address adverse effects of estradiol on atherosclerosis, endothelial function, and thrombosis in a murine model of atherosclerosis. ApoE−/− mice were bilaterally ovariectomized (OVX) and substituted with placebo or 17-β-Estradiol (E2, 1.1 and 6.6 μg/day) on Western diet for 90 days. Low-dose E2 (1.1 μg/day) treatment significantly increased atherosclerotic plaque score, whereas high-dose E2 (6.6 μg/day) reduced aortic plaque burden. The proatherosclerotic effects of low-dose E2 were associated with decreased total collagen in aortic root lesions and impaired acetylcholine (ACh)-induced vasorelaxation of aortic rings. On the contrary, OVX compared with control reduced atherosclerosis, increased fibrillar collagen and improved endothelial function. The thrombotic response as measured in a photothrombosis model was not significantly altered by E2 or OVX. Taken together, differential effects on atherosclerosis of the clinical relevant low-dose E2 compared with high-dose E2 were demonstrated. Importantly, the presented experimental conditions provide a model to study the untoward vascular effects of E2 in the context of accelerated and advanced atherosclerosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Notes

  1. Endothelium independent relaxation to the NO-donor S-nitroso-N-acetylpenicillamine (SNAP) was not changed in response to E2 (data not shown).

  2. In contrast, relaxation of aortic rings in response to SNAP was not altered by OVX (data not shown).

References

  1. Abbas A, Fadel PJ, Wang Z, Arbique D, Jialal I, Vongpatanasin W (2004) Contrasting effects of oral versus transdermal estrogen on serum amyloid A (SAA) and high-density lipoprotein-SAA in postmenopausal women. Arterioscler Thromb Vasc Biol 24:e164–e167

    Article  CAS  PubMed  Google Scholar 

  2. Al-Azzawi F (2002) Pulsed estrogen therapy: from cellular mode of action to tissue effects. Climacteric 5(suppl 2):27–31

    Google Scholar 

  3. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, Margolis K, Ockene J, O’Sullivan MJ, Phillips L, Prentice RL, Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML, Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291:1701–1712

    Article  CAS  PubMed  Google Scholar 

  4. Barrett-Connor E (2007) Hormones and heart disease in women: the timing hypothesis. Am J Epidemiol 166:506–510

    Article  PubMed  Google Scholar 

  5. Bourassa PA, Milos PM, Gaynor BJ, Breslow JL, Aiello RJ (1996) Estrogen reduces atherosclerotic lesion development in apolipoprotein E-deficient mice. Proc Natl Acad Sci USA 93:10022–10027

    Article  CAS  PubMed  Google Scholar 

  6. d’Uscio LV, Smith LA, Katusic ZS (2001) Hypercholesterolemia impairs endothelium-dependent relaxations in common carotid arteries of apolipoprotein e-deficient mice. Stroke 32:2658–2664

    Article  PubMed  Google Scholar 

  7. Dai G, Freudenberger T, Zipper P, Melchior A, Grether-Beck S, Rabausch B, de Groot J, Twarock S, Hanenberg H, Homey B, Krutmann J, Reifenberger J, Fischer JW (2007) Chronic ultraviolet B irradiation causes loss of hyaluronic acid from mouse dermis because of down-regulation of hyaluronic acid synthases. Am J Pathol 171:1451–1461

    Article  CAS  PubMed  Google Scholar 

  8. Darblade B, Pendaries C, Krust A, Dupont S, Fouque MJ, Rami J, Chambon P, Bayard F, Arnal JF (2002) Estradiol alters nitric oxide production in the mouse aorta through the alpha-, but not beta-, estrogen receptor. Circ Res 90:413–419

    Article  CAS  PubMed  Google Scholar 

  9. Elhage R, Arnal JF, Pieraggi MT, Duverger N, Fievet C, Faye JC, Bayard F (1997) 17 beta-estradiol prevents fatty streak formation in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 17:2679–2684

    CAS  PubMed  Google Scholar 

  10. Elhage R, Maret A, Pieraggi MT, Thiers JC, Arnal JF, Bayard F (1998) Differential effects of interleukin-1 receptor antagonist and tumor necrosis factor binding protein on fatty-streak formation in apolipoprotein E-deficient mice. Circulation 97:242–244

    CAS  PubMed  Google Scholar 

  11. Grodstein F, Stampfer M (1995) The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women. Prog Cardiovasc Dis 38:199–210

    Article  CAS  PubMed  Google Scholar 

  12. Hermenegildo C, Oviedo PJ, Laguna A, Garcia-Perez MA, Tarin JJ, Cano A (2008) Transdermal estradiol reduces F2alpha-isoprostane levels in postmenopausal women. Menopause 15:714–717

    Article  PubMed  Google Scholar 

  13. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 280:605–613

    Article  CAS  PubMed  Google Scholar 

  14. Koh KK, Son JW, Ahn JY, Lee SK, Hwang HY, Kim DS, Jin DK, Ahn TH, Shin EK (2001) Effect of hormone replacement therapy on nitric oxide bioactivity and monocyte chemoattractant protein-1 levels. Int J Cardiol 81:43–50

    Article  CAS  PubMed  Google Scholar 

  15. Lam KK, Lee YM, Hsiao G, Chen SY, Yen MH (2006) Estrogen therapy replenishes vascular tetrahydrobiopterin and reduces oxidative stress in ovariectomized rats. Menopause 13:294–302

    Article  PubMed  Google Scholar 

  16. Mendelsohn ME, Karas RH (1999) The protective effects of estrogen on the cardiovascular system. N Engl J Med 340:1801–1811

    Article  CAS  PubMed  Google Scholar 

  17. Mikkola TS, Clarkson TB (2002) Estrogen replacement therapy, atherosclerosis, and vascular function. Cardiovasc Res 53:605–619

    Article  CAS  PubMed  Google Scholar 

  18. Montague CR, Hunter MG, Gavrilin MA, Phillips GS, Goldschmidt-Clermont PJ, Marsh CB (2006) Activation of estrogen receptor-alpha reduces aortic smooth muscle differentiation. Circ Res 99:477–484

    Article  CAS  PubMed  Google Scholar 

  19. Pervin S, Singh R, Rosenfeld ME, Navab M, Chaudhuri G, Nathan L (1998) Estradiol suppresses MCP-1 expression in vivo: implications for atherosclerosis. Arterioscler Thromb Vasc Biol 18:1575–1582

    CAS  PubMed  Google Scholar 

  20. Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362:801–809

    Article  CAS  PubMed  Google Scholar 

  21. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 288:321–333

    Article  CAS  PubMed  Google Scholar 

  22. Suvorava T, Lauer N, Kumpf S, Jacob R, Meyer W, Kojda G (2005) Endogenous vascular hydrogen peroxide regulates arteriolar tension in vivo. Circulation 112:2487–2495

    Article  CAS  PubMed  Google Scholar 

  23. Vickers MR, MacLennan AH, Lawton B, Ford D, Martin J, Meredith SK, DeStavola BL, Rose S, Dowell A, Wilkes HC, Darbyshire JH, Meade TW (2007) Main morbidities recorded in the women’s international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women. BMJ 335:239

    Article  CAS  PubMed  Google Scholar 

  24. Wassmann S, Czech T, van Eickels M, Fleming I, Bohm M, Nickenig G (2004) Inhibition of diet-induced atherosclerosis and endothelial dysfunction in apolipoprotein E/angiotensin II type 1A receptor double-knockout mice. Circulation 110:3062–3067

    Article  CAS  PubMed  Google Scholar 

  25. Wilson KM, Lynch CM, Faraci FM, Lentz SR (2003) Effect of mechanical ventilation on carotid artery thrombosis induced by photochemical injury in mice. J Thromb Haemost 1:2669–2674

    Article  CAS  PubMed  Google Scholar 

  26. Yoshida T, Gan Q, Shang Y, Owens GK (2007) Platelet-derived growth factor-BB represses smooth muscle cell marker genes via changes in binding of MKL factors and histone deacetylases to their promoters. Am J Physiol Cell Physiol 292:C886–895

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

Bundesinstitut für Arzneimittel und Medizinprodukte.

Author information

Authors and Affiliations

  1. Institut für Pharmakologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstrasse, 55, 45122, Essen, Germany

    Till Freudenberger & Jens W. Fischer

  2. Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität, Düsseldorf, Germany

    Marc Oppermann, Georg Kojda & Karsten Schrör

  3. Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), Bonn, Germany

    Hans-Karl Heim & Peter Mayer

Authors
  1. Till Freudenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marc Oppermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hans-Karl Heim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Mayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Georg Kojda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karsten Schrör
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jens W. Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jens W. Fischer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Freudenberger, T., Oppermann, M., Heim, HK. et al. Proatherogenic effects of estradiol in a model of accelerated atherosclerosis in ovariectomized ApoE-deficient mice. Basic Res Cardiol 105, 479–486 (2010). https://doi.org/10.1007/s00395-010-0091-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00395-010-0091-6

Keywords

Search

Navigation