Hostname: page-component-7f64f4797f-7vqc4 Total loading time: 0 Render date: 2025-11-03T12:15:14.920Z Has data issue: false hasContentIssue false
  • English
  • Français

Isoflavones and endothelial function

Published online by Cambridge University Press:  14 December 2007

Wendy L. Hall ,
Gerald Rimbach  and
Christine M. Williams
Wendy L. Hall*
Affiliation:
Hugh Sinclair Unit of Human Nutrition, School of Food Biosciences, University of Reading, PO Box 226, Reading RG6 6AP, UK
Gerald Rimbach
Affiliation:
Institute of Human Nutrition and Food Science, Christian Albrechts University, Olhausenstrasse 40, D-24 098 Kiel, Germany
Christine M. Williams
Affiliation:
Hugh Sinclair Unit of Human Nutrition, School of Food Biosciences, University of Reading, PO Box 226, Reading RG6 6AP, UK
*
*Corresponding author: Dr Wendy Hall, fax +44 118 9310080, email w.l.hall@reading.ac.uk
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Dietary isoflavones are thought to be cardioprotective due to their structural similarity to oestrogen. Oestrogen is believed to have beneficial effects on endothelial function and may be one of the mechanisms by which premenopausal women are protected against CVD. Decreased NO production and endothelial NO synthase activity, and increased endothelin-1 concentrations, impaired lipoprotein metabolism and increased circulating inflammatory factors result from oestrogen deficiency. Oestrogen acts by binding to oestrogen receptors α and β. Isoflavones have been shown to bind with greater affinity to the latter. Oestrogen replacement therapy is no longer thought to be a safe treatment for prevention of CVD; isoflavones are a possible alternative. Limited evidence from human intervention studies suggests that isoflavones may improve endothelial function, but the available data are not conclusive. Animal studies provide stronger support for a role of isoflavones in the vasculature, with increased vasodilation and endothelial NO synthase activity demonstrated. Cellular mechanisms underlying the effects of isoflavones on endothelial cell function are not yet clear. Possible oestrogen receptor-mediated pathways include modulation of gene transcription, and also non-genomic oestrogen receptor-mediated signalling pathways. Putative non-oestrogenic pathways include inhibition of reactive oxygen species production and up regulation of the protein kinase A pathway (increasing NO bioavailability). Further research is needed to unravel effects of isoflavones on intracellular regulation of the endothelial function. Moreover, there is an urgent need for adequately powered, robustly designed human intervention studies in order to clarify the present equivocal findings.

Keywords

IsoflavonesEndothelial functionOestrogenCardiovascular disease

Information

Type
Research Articles
Information
Nutrition Research Reviews , Volume 18 , Issue 1 , June 2005 , pp. 130 - 144
Copyright
Copyright © The Authors 2005

References

Aavik, E, du Toit, D, Myburgh, E, Frosen, J & Hayry, P (2001) Estrogen receptor beta dominates in baboon carotid after endothelial denudation injury. Molecular and Cellular Endocrinology 182, 91–98.CrossRefGoogle ScholarPubMed
Adams, MR, Williams, JK & Kaplan, JR (1995) Effects of androgens on coronary artery atherosclerosis and atherosclerosis-related impairment of vascular responsiveness. Arteriosclerosis Thrombosis and Vascular Biology 15, 562–570.Google Scholar
Adlercreutz, H, Markkanen, H & Watanabe, S (1993) Plasma concentrations of phyto oestrogens in Japanese men. Lancet 342, 1209–1210.CrossRefGoogle ScholarPubMed
Akashita, M, Ouchi, Y, Miyoshi, H, Orimo, A, Kozaki, K, Eto, M, Ishikawa, M, Kim, S, Toba, K & Orimo, H (1996) Estrogen inhibits endothelin-1 production and c-fos gene expression in rat aorta. Atherosclerosis 125, 27–38.CrossRefGoogle Scholar
Ambra, R, Rimbach, G, de Pascual-Teresa, S, Wenzel, U, Daniel, H & Virgili, F (2005) Genistein affects the expression of genes involved in blood pressure regulation and angiogenesis in primary human endothelial cells. Nutrition Metabolism and Cardiovascular Diseases (In the Press).Google Scholar
An, J, Tzagarakis-Foster, C, Scharschmidt, TC, Lomri, N & Leitman, DC (2001) Estrogen receptor beta-selective transcriptional activity and recruitment of coregulators by phytoestrogens. Journal of Biological Chemistry 276, 17808–17814.Google Scholar
Arai, Y, Watanabe, S, Kimira, M, Shimoi, K, Mochizuki, R & Kinae, N (2000) Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. Journal of Nutrition 130, 2243–2250.Google Scholar
Atkinson, C, Oosthuizen, W, Scollen, S, Loktionov, A, Day, NE & Bingham, SA (2004) Modest protective effects of isoflavones from a red clover-derived dietary supplement on cardiovascular disease risk factors in perimenopausal women, and evidence of an interaction with ApoE genotype in 49–65 year-old women. Journal of Nutrition 134, 1759–1764.CrossRefGoogle ScholarPubMed
Beaglehole, R (1990) International trends in coronary heart disease mortality, morbidity, and risk factors. Epidemiological Reviews 12, 1–15.CrossRefGoogle ScholarPubMed
Beral, V & Million Women Study Collaborators (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362, 419–427.CrossRefGoogle ScholarPubMed
Bingham, M, Gibson, G, Gottstein, N, de Pascual-Teresa, S, Minihane, A-M & Rimbach, G (2003) Gut metabolism and cardioprotective effects of dietary isoflavones. Current Topics in Nutraceutical Research 1, 31–48.Google Scholar
Blann, AD (1993) Is raised von Willebrand factor a marker of endothelial cell damage? Medical Hypotheses 41, 419–424.CrossRefGoogle ScholarPubMed
Brevetti, G, Martone, VD, de Cristofaro, T, Corrado, S, Silvestro, A, Di Donato, AM, Bucur, R & Scopacasa, F (2001) High levels of adhesion molecules are associated with impaired endothelium-dependent vasodilation in patients with peripheral arterial disease. Thrombosis and Haemostasis 85, 63–66.Google ScholarPubMed
Brouchet, L, Krust, A, Dupont, S, Chambon, P, Bayard, F & Arnal, JF (2001) Estradiol accelerates reendothelialization in mouse carotid artery through estrogen receptor alpha but not estrogen receptor-beta. Circulation 103, 423–428.Google Scholar
Bush, DE, Jones, CE, Bass, KM, Walters, GK, Bruza, JM & Ouyang, P (1998) Estrogen replacement reverses endothelial dysfunction in postmenopausal women. American Journal of Medicine 104, 552–558.Google Scholar
Caballero, AE, Arora, S, Saouaf, R, Lim, SC, Smakowski, P, Park, JY, King, GL, LoGerfo, FW, Horton, ES & Veves, A (1999) Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes 48, 1856–1862.Google Scholar
Cai, H & Harrison, DG (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circulation Research 87, 840–844.Google Scholar
Cassidy, A, De Pascual Teresa, S & Rimbach, G (2003) Molecular mechanisms by which dietary isoflavones potentially prevent atherosclerosis. Acta Obstetricia et Gynecologica Scandinavica 5, 1–15.Google ScholarPubMed
Catania, MA, Crupi, A, Firenzuoli, F, Parisi, A, Sturiale, A, Squadrito, F, Caputi, AP & Calapai, G (2002) Oral administration of a soy extract improves endothelial dysfunction in ovariectomized rats. Planta Medica 68, 1142–1144.CrossRefGoogle ScholarPubMed
Celermajer, DS, Sorensen, KE, Gooch, VM, Spiegelhalter, DJ, Miller, OI, Sullivan, ID, Lloyd, JK & Deanfield, JE (1992) Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340, 1111–1115.Google Scholar
Chambliss, KL & Shaul, PW (2002); Estrogen modulation of endothelial nitric oxide synthase. Endocrinology Reviews 23, 665–686.CrossRefGoogle ScholarPubMed
Chambliss, KL, Yuhanna, IS, Mineo, C, Liu, P, German, Z, Sherman, TS, Mendelsohn, ME, Anderson, RG & Shaul, PW (2000) Estrogen receptor alpha and endothelial nitric oxide synthase are organized into a functional signaling module in caveolae. Circulation Research 87, E44–E52.CrossRefGoogle ScholarPubMed
Chen, C, Conklin, BS, Ren, Z & Zhong, DS (2002) Homocysteine decreases endothelium-dependent vasorelaxation in porcine arteries. Journal of Surgical Research 102, 22–30.Google Scholar
Chin-Dusting, JP, Boak, L, Husband, A & Nestel, PJ (2004) The isoflavone metabolite dehydroequol produces vasodilatation in human resistance arteries via a nitric oxide-dependent mechanism. Atherosclerosis 176, 45–48.CrossRefGoogle Scholar
Chin-Dusting, JP, Fisher, LJ, Lewis, TV, Piekarska, A, Nestel, PJ & Husband, A (2001) The vascular activity of some isoflavone metabolites: implications for a cardioprotective role. British Journal of Pharmacology 133, 595–605.CrossRefGoogle ScholarPubMed
Cowley, SM, Hoare, S, Mosselman, S & Parker, MG. (1997) Estrogen receptors alpha and beta form heterodimers on DNA. Journal of Biological Chemistry 272, 19858–19862.Google Scholar
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. Circulation Research 90, 413–419.CrossRefGoogle Scholar
Davis, JN, Kucuk, O, Djuric, Z & Sarkar, FH (2001) Soy isoflavone supplementation in healthy men prevents NF-kappa B activation by TNF-alpha in blood lymphocytes. Free Radical Biology and Medicine 30, 1293–1302.CrossRefGoogle ScholarPubMed
De Kleijn, MJ, van der Schouw, YT, Wilson, PW, Adlercreutz, H, Mazur, W, Grobbee, DE & Jacques, PF (2001) Intake of dietary phytoestrogens is low in postmenopausal women in the United States: the Framingham study (1–4). Journal of Nutrition 131, 1826–1832.Google Scholar
Evans, MJ, Eckert, A, Lai, K, Adelman, SJ & Harnish, DC (2001) Reciprocal antagonism between estrogen receptor and NF-kappaB activity in vivo. Circulation Research 89, 823–830.Google Scholar
Farkas, K, Kolossvary, E, Jarai, Z, Nemcsik, J & Farsang, C (2004) Non-invasive assessment of microvascular endothelial function by laser Doppler flowmetry in patients with essential hypertension. Atherosclerosis 173, 97–102.CrossRefGoogle ScholarPubMed
Fichtlscherer, S, Breuer, S, Schachinger, V, Dimmeler, S & Zeiher, AM (2004) C-reactive protein levels determine systemic nitric oxide bioavailability in patients with coronary artery disease. European Heart Journal 25, 1412–1418.Google Scholar
Fichtlscherer, S, Rosenberger, G, Walter, DH, Breuer, S, Dimmeler, S & Zeiher, AM (2000) Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation 102, 1000–1006.Google Scholar
Floter, A, Nathorst-Boos, J, Carlstrom, K & von Schoultz, B (2004) Serum lipids in oophorectomized women during estrogen and testosterone replacement therapy. Maturitas 47, 123–129.CrossRefGoogle ScholarPubMed
Frankenfeld, CL, Lampe, JW, Shannon, J, Gao, DL, Ray, RM, Prunty, J, Kalhorn, TF, Wähälä, K, Patterson, RE & Thomas, DB (2004) Frequency of soy food consumption and serum isoflavone concentrations among Chinese women in Shanghai. Public Health Nutrition 7, 765–772.CrossRefGoogle ScholarPubMed
Garcia-Martinez, MC, Hermenegildo, C, Tarin, JJ & Cano, A (2003) Phytoestrogens increase the capacity of serum to stimulate prostacyclin release in human endothelial cells. Acta Obstetricia et Gynecologica Scandinavica 82, 705–710.Google Scholar
Gilligan, DM, Quyyumi, AA & Cannon, RO III (1994) Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women. Circulation 89, 2545–2551.CrossRefGoogle ScholarPubMed
Gisclard, V, Miller, VM & Vanhoutte, PM (1988) Effect of 17 beta-estradiol on endothelium-dependent responses in the rabbit. Journal of Pharmacology and Experimental Therapeutics 244, 19–22.Google ScholarPubMed
Gokce, N, Keaney, JF Jr, Hunter, LM, Watkins, MT, Nedeljkovic, ZS, Menzoian, JO & Vita, JA (2003) Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. Journal of the American College of Cardiology 41, 1769–1775.Google Scholar
Gottstein, N, Ewins, BA, Eccleston, C, Hubbard, GP, Kavanagh, IC, Minihane, AM, Weinberg, PD & Rimbach, G (2003) Effect of genistein and daidzein on platelet aggregation and monocyte and endothelial function. British Journal of Nutrition 89, 607–616.Google Scholar
Green, S, Walter, P, Greene, G, Krust, A, Goffin, C, Jensen, E, Scrace, G, Waterfield, M & Chambon, P (1986) Cloning of the human oestrogen receptor cDNA. Journal of Steroid Biochemistry 24, 77–83.Google Scholar
Greene, GL, Gilna, P, Waterfield, M, Baker, A, Hort, Y & Shine, J (1986) Sequence and expression of human estrogen receptor complementary DNA. Science 231, 1150–1154.Google Scholar
Guo, Q, Rimbach, G, Moini, H, Weber, S & Packer, L (2002) ESR and cell culture studies on free radical-scavenging and antioxidant activities of isoflavonoids. Toxicology 179, 171–180.CrossRefGoogle ScholarPubMed
Hale, G, Paul-Labrador, M, Dwyer, JH & Merz, CN (2002) Isoflavone supplementation and endothelial function in menopausal women. Clinical Endocrinology 56, 693–701.Google Scholar
Hambrecht, R, Adams, V, Erbs, S, Linke, A, Krankel, N, Shu, Y, Baither, Y, Gielen, S, Thiele, H, Gummert, JF, Mohr, FW & Schuler, G (2003) Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation 107, 3152–3158.Google Scholar
Hansell, J, Henareh, L, Agewall, S & Norman, M (2004) Non-invasive assessment of endothelial function – relation between vasodilatory responses in skin microcirculation and brachial artery. Clinical Physiology and Functional Imaging 24, 317–322.CrossRefGoogle ScholarPubMed
Hayden, MR & Tyagi, SC (2003) Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress. Cardiovascular Diabetology 2, 2.CrossRefGoogle ScholarPubMed
Heitzer, T, Schlinzig, T, Krohn, K, Meinertz, T & Munzel, T (2001) Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 104, 2673–2678.CrossRefGoogle ScholarPubMed
Hernandez, I, Delgado, JL, Diaz, J, Quesada, T, Teruel, MJ, Llanos, MC & Carbonell, LF (2000) 17Beta-estradiol prevents oxidative stress and decreases blood pressure in ovariectomized rats. American Journal of Physiology 279, R1599–R1605.Google Scholar
Hodges, YK, Tung, L, Yan, XD, Graham, JD, Horwitz, KB & Horwitz, LD (2000) Estrogen receptors alpha and beta: prevalence of estrogen receptor beta mRNA in human vascular smooth muscle and transcriptional effects. Circulation 101, 1792–1798.Google Scholar
Hodgson, JM, Puddey, IB, Croft, KD, Mori, TA, Rivera, J & Beilin, LJ (1999) Isoflavonoids do not inhibit in vivo lipid peroxidation in subjects with high-normal blood pressure. Atherosclerosis 145, 167–172.CrossRefGoogle Scholar
Holden, DP, Cartwright, JE, Nussey, SS & Whitley, GS (2003) Estrogen stimulates dimethylarginine dimethylaminohydrolase activity and the metabolism of asymmetric dimethylarginine. Circulation 108, 1575–1580.Google Scholar
Horn-Ross, PL, Barnes, S, Lee, M, Coward, L, Mandel, JE, Koo, J, John, EM & Smith, M (2000) Assessing phytoestrogen exposure in epidemiologic studies: development of a database (United States). Cancer Causes and Control 11, 289–298.Google Scholar
Hwang, J, Wang, J, Morazzoni, P, Hodis, HN & Sevanian, A (2003) The phytoestrogen equol increases nitric oxide availability by inhibiting superoxide production: an antioxidant mechanism for cell-mediated LDL modification. Free Radical Biology and Medicine 34, 1271–1282.Google Scholar
Hwang, SJ, Ballantyne, CM, Sharrett, AR, Smith, LC, Davis, CE, Gotto, AM Jr & Boerwinkle, E (1997) Circulating adhesion molecules VCAM-1, ICAM-1, and E selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study. Circulation 96, 4219–4225.Google Scholar
Ishibashi, T, Yoshida, J & Nishio, M (1999) Evaluation of NOx in the cardiovascular system: relationship to NO-related compounds in vivo. Japanese Journal of Pharmacology 81, 317–323.Google Scholar
Ji, ES, Li, Q & He, RR (2002) Action of genistein on tension of isolated rabbit femoral artery and its mechanism. Sheng Li Xue Bao 54, 422–426.Google Scholar
Jiang, F, Jones, GT, Husband, AJ & Dusting, GJ (2003) Cardiovascular protective effects of synthetic isoflavone derivatives in apolipoprotein e-deficient mice. Journal of Vascular Research 40, 276–284.CrossRefGoogle ScholarPubMed
Kannel, WB & Wilson, PW (1995) Risk factors that attenuate the female coronary disease advantage. Archives of Internal Medicine 155, 57–61.CrossRefGoogle ScholarPubMed
Karamsetty, MR, Klinger, JR & Hill, NS (2001) Phytoestrogens restore nitric oxide mediated relaxation in isolated pulmonary arteries from chronically hypoxic rats. Journal of Pharmacology and Experimental Therapeutics 297, 968–974.Google Scholar
Karas, RH, Hodgin, JB, Kwoun, M, Krege, JH, Aronovitz, M, Mackey, W, Gustafsson, JA, Korach, KS, Smithies, O & Mendelsohn, ME (1999) Estrogen inhibits the vascular injury response in estrogen receptor beta-deficient female mice. Proceedings of the National Academy of Sciences USA 96, 15133–15136.Google Scholar
Karas, RH, Schulten, H, Pare, G, Aronovitz, MJ, Ohlsson, C, Gustafsson, JA & Mendelsohn, ME (2001) Effects of estrogen on the vascular injury response in estrogen receptor alpha, beta (double) knockout mice. Circulation Research 89, 534–539.Google Scholar
Keinan-Boker, L, Peeters, PH, Mulligan, AA, Navarro, C, Slimani, N, Mattisson, I, Lundin, E, McTaggart, A, Allen, NE, Overvad, K, Tjonneland, A & Clavel-Chapelon, F (2002) Soy product consumption in 10 European countries: the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Public Health Nutrition 5, 1217–1226.CrossRefGoogle ScholarPubMed
Kerry, N & Abbey, M (1998) The isoflavone genistein inhibits copper and peroxyl radical mediated low density lipoprotein oxidation in vitro. Atherosclerosis 140, 341–347.Google Scholar
Kleinbongard, P, Dejam, A, Lauer, T, Rassaf, T, Schindler, A, Picker, O, Scheeren, T, Godecke, A, Schrader, J, Schulz, R, Heusch, G & Schaub, GA (2003) Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals. Free Radical Biology and Medicine 35, 790–796.Google Scholar
Koh, KK, Bui, MN, Mincemoyer, R & Cannon, RO III (1997 a) Effects of hormone therapy on inflammatory cell adhesion molecules in postmenopausal healthy women. American Journal of Cardiology 80, 1505–1507.Google Scholar
Koh, KK, Jin, DK, Yang, SH, Lee, SK, Hwang, HY, Kang, MH, Kim, W, Kim, DS, Choi, IS & Shin, EK (2001) Vascular effects of synthetic or natural progestagen combined with conjugated equine estrogen in healthy postmenopausal women. Circulation 103, 1961–1966.Google Scholar
Koh, KK, Mincemoyer, R, Bui, MN, Csako, G, Pucino, F, Guetta, V, Waclawiw, M & Cannon, RO III (1997 b) Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women. New England Journal of Medicine 336, 683–690.CrossRefGoogle ScholarPubMed
Kostelac, D, Rechkemmer, G & Briviba, K (2003) Phytoestrogens modulate binding response of estrogen receptors alpha and beta to the estrogen response element. Journal of Agricultural and Food Chemistry 51, 7632–7635.Google Scholar
Krasinski, K, Spyridopoulos, I, Asahara, T, van der Zee, R, Isner, JM & Losordo, DW (1997) Estradiol accelerates functional endothelial recovery after arterial injury. Circulation 95, 1768–1772.Google Scholar
Kreijkamp-Kaspers, S, Kok, L, Bots, ML, Grobbee, DE & van der Schouw, YT (2004) Dietary phytoestrogens and vascular function in postmenopausal women: a cross-sectional study. Journal of Hypertension 22, 1381–1388.Google Scholar
Kuiper, GG, Enmark, E, Pelto-Huikko, M, Nilsson, S & Gustafsson, JA (1996) Cloning of a novel receptor expressed in rat prostate and ovary. Proceedings of the National Academy of Sciences USA 93, 5925–5930.Google Scholar
Kuller, LH (2003) Hormone replacement therapy and risk of cardiovascular disease: implications of the results of the Women's Health Initiative. Arteriosclerosis Thrombosis and Vascular Biology 23, 11–16.Google Scholar
Lauer, T, Preik, M, Rassauf, T, Strauer, BE, Deussen, A, Feelisch, M & Kelm, M (2001) Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action. Proceedings of the National Academy of Sciences USA 98, 12814–12819.CrossRefGoogle ScholarPubMed
Lauer, T, Kleinbongard, P & Kelm, M (2002) Indexes of NO bioavailability in human blood. News in Physiological Sciences 17, 251–255.Google Scholar
Lawlor, DA, Ebrahim, S & Smith, GD (2003) The association of socio-economic position across the life course and age at menopause: the British Women's Heart and Health Study. British Journal of Obstetrics and Gynaecology 110, 1078–1087.Google Scholar
Lee, MY & Man, RY (2003) The phytoestrogen genistein enhances endothelium-independent relaxation in the porcine coronary artery. European Journal of Pharmacology 481, 227–232.Google Scholar
Li, HF, Wang, LD & Qu, SY (2004) Phytoestrogen genistein decreases contractile response of aortic artery in vitro and arterial blood pressure in vivo. Acta Pharmacologica Sinica 25, 313–318.Google Scholar
Lidington, EA, Moyes, DL, McCormack, AM & Rose, ML (1999) A comparison of primary endothelial cells and endothelial cell lines for studies of immune interactions. Transplant Immunology 7, 239–246.CrossRefGoogle ScholarPubMed
Lieberman, EH, Gerhard, MD, Uehata, A, Walsh, BW, Selwyn, AP, Ganz, P, Yeung, AC & Creager, MA (1994) Estrogen improves endothelium-dependent, flow-mediated vasodilation in postmenopausal women. Annals of Internal Medicine 121, 936–941.Google Scholar
Lindner, V, Kim, SK, Karas, RH, Kuiper, GG, Gustafsson, JA & Mendelsohn, ME (1998) Increased expression of estrogen receptor-beta mRNA in male blood vessels after vascular injury. Circulation Research 83, 224–229.Google Scholar
Lissin, LW, Oka, R, Lakshmi, S & Cooke, JP (2004) Isoflavones improve vascular reactivity in post-menopausal women with hypercholesterolemia. Vascular Medicine 9, 26–30.Google Scholar
Liu, D, Homan, LL & Dillon, JS (2004 a) Genistein acutely stimulates nitric oxide synthesis in vascular endothelial cells by a cyclic adenosine 5'-monophosphate-dependent mechanism. Endocrinology 145, 5532–5539.Google Scholar
Liu, Z, Li, W, Sun, J, Liu, C, Zeng, Q, Huang, J, Yu, B & Huo, J (2004 b) Intake of soy foods and soy isoflavones by rural adult women in China. Asia Pacific Journal of Clinical Nutrition 13, 204–209.Google Scholar
Ludmer, PL, Selwyn, AP, Shook, TL, Wayne, RR, Mudge, GH, Alexander, RW & Ganz, P (1986) Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. New England Journal of Medicine 315, 1046–1051.Google Scholar
McCrohon, JA, Adams, MR, McCredie, RJ, Robinson, J, Pike, A, Abbey, M, Keech, AC & Celermajer, DS (1996) Hormone replacement therapy is associated with improved arterial physiology in healthy post menopausal women. Clinical Endocrinology 45, 435–441.Google Scholar
McGregor, PE, Agrawal, DK & Edwards, JD (1994) Attenuation of human leukocyte adherence to endothelial cell monolayers by tyrosine kinase inhibitors. Biochemical and Biophysical Research Communications 198, 359–365.Google Scholar
Makila, UM, Wahlberg, L, Vlinikka, L & Ylikorkala, O (1982) Regulation of prostacyclin and thromboxane production by human umbilical vessels: the effect of estradiol and progesterone in a superfusion model. Prostaglandins Leukotrienes and Medicine 8, 115–124.Google Scholar
May, MJ, Wheeler-Jones, CP & Pearson, JD (1996) Effects of protein tyrosine kinase inhibitors on cytokine-induced adhesion molecule expression by human umbilical vein endothelial cells. British Journal of Pharmacology 118, 1761–1771.Google Scholar
Meng, QH, Lewis, P, Wahala, K, Adlercreutz, H & Tikkanen, MJ (1999) Incorporation of esterified soybean isoflavones with antioxidant activity into low density lipoprotein. Biochimica et Biophysica Acta 1438, 369–376.Google Scholar
Micheli, A, Baili, P, Quinn, M, Mugno, E, Capocaccia, R & Grosclaude, P (2003) EUROCARE Working Group Life expectancy and cancer survival in the EUROCARE-3 cancer registry areas. Annals of Oncology 14, Suppl. 5, V28–V40.Google Scholar
Mikkola, T, Ranta, V, Orpana, A, Viinikka, L & Ylikorkala, O (1996) Hormone replacement therapy modifies the capacity of plasma and serum to regulate prostacyclin and endothelin-1 production in human vascular endothelial cells. Fertility and Sterility 66, 389–393.Google Scholar
Miksicek, RJ (1993) Commonly occurring plant flavonoids have estrogenic activity. Molecular Pharmacology 44, 37–43.Google Scholar
Morito, K, Hirose, T, Kinjo, J, Hirakawa, T, Okawa, M, Nohara, T, Ogawa, S, Inoue, S, Muramatsu, M & Masamune, Y (2001) Interaction of phytoestrogens with estrogen receptors alpha and beta. Biological and Pharmaceutical Bulletin 24, 351–356.Google Scholar
Morris, SJ & Shore, AC (1996) Skin blood flow responses to the iontophoresis of acetylcholine and sodium nitroprusside in man: possible mechanisms. Journal of Physiology 496, 531–542.Google Scholar
Mosselman, S, Polman, J & Dijkema, R (1996) ER beta: identification and characterization of a novel human estrogen receptor. FEBS Letters 392, 49–53.Google Scholar
Mukherjee, TK, Nathan, L, Dinh, H, Reddy, ST & Chaudhuri, G (2003) 17-Epiestriol, an estrogen metabolite, is more potent than estradiol in inhibiting vascular cell adhesion molecule 1 (VCAM-1) mRNA expression. Journal of Biological Chemistry 278, 11746–11752.Google Scholar
Nakashima, S, Koike, T & Nozawa, Y (1991) Genistein, a protein tyrosine kinase inhibitor, inhibits thromboxane A2-mediated human platelet responses. Molecular Pharmacology 39, 475–480.Google Scholar
Nelson, HD, Humphrey, LL, Nygren, P, Teutsch, SM & Allan, JD (2002) Postmenopausal hormone replacement therapy: scientific review. Journal of the American Medical Association 288, 872–881.Google Scholar
Nestel, PJ, Pomeroy, S, Kay, S, Komesaroff, P, Behrsing, J, Cameron, JD & West, L (1999) Isoflavones from red clover improve systemic arterial compliance but not plasma lipids in menopausal women. Journal of Clinical Endocrinology and Metabolism 84, 895–898.Google Scholar
Nestel, PJ, Yamashita, T, Sasahara, T, Pomeroy, S, Dart, A, Komesaroff, P, Owen, A & Abbey, M (1997) Soy isoflavones improve systemic arterial compliance but not plasma lipids in menopausal and perimenopausal women. Arteriosclerosis Thrombosis and Vascular Biology 17, 3392–3398.CrossRefGoogle Scholar
Neunteufl, T, Katzenschlager, R, Hassan, A, Klaar, U, Schwarzacher, S, Glogar, D, Bauer, P & Weidinger, F (1997) Systemic endothelial dysfunction is related to the extent and severity of coronary artery disease. Atherosclerosis 129, 111–118.Google Scholar
Nevala, R, Korpela, R & Vapaatalo, H (1998) Plant derived estrogens relax rat mesenteric artery in vitro. Life Sciences 63, PL95–PL100.CrossRefGoogle ScholarPubMed
Nigam, A, Mitchell, GF, Lambert, J & Tardif, JC (2003) Relation between conduit vessel stiffness (assessed by tonometry) and endothelial function (assessed by flow-mediated dilatation) in patients with and without coronary heart disease. American Journal of Cardiology 92, 395–399.CrossRefGoogle ScholarPubMed
Nikander, E, Metsa-Heikkila, M, Tiitinen, A & Ylikorkala, O (2003) Evidence of a lack of effect of a phytoestrogen regimen on the levels of C-reactive protein, E-selectin, and nitrate in postmenopausal women. Journal of Clinical Endocrinology and Metabolism 88, 5180–5185.Google Scholar
Omland, T, Lie, RT, Aakvaag, A, Aarsland, T & Dickstein, K (1994) Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction. Circulation 89, 1573–1579.CrossRefGoogle ScholarPubMed
Paech, K, Webb, P, Kuiper, GG, Nilsson, S, Gustafsson, J, Kushner, PJ & Scanlan, TS (1997) Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites. Science 277, 1508–1510.CrossRefGoogle ScholarPubMed
Paganini-Hill, A, Dworsky, R & Krauss, RM (1996) Hormone replacement therapy, hormone levels, and lipoprotein cholesterol concentrations in elderly women. American Journal of Obstetrics and Gynecology 174, 897–902.Google Scholar
Pare, G, Krust, A, Karas, RH, Dupont, S, Aronovitz, M, Chambon, P & Mendelsohn, ME (2002) Estrogen receptor-alpha mediates the protective effects of estrogen against vascular injury. Circulation Research 90, 1087–1092.Google Scholar
Quyyumi, AA, Dakak, N, Andrews, NP, Gilligan, DM, Panza, JA & Cannon, RO III (1995) Contribution of nitric oxide to metabolic coronary vasodilation in the human heart. Circulation 92, 320–326.Google Scholar
Ranta, V, Orpana, A, Mikkola, T, Ylikorkala, O & Viinikka, L (1997) Culturing of human vascular endothelial cells strongly affects their endothelin-1 and prostacyclin production. Molecular and Cellular Biochemistry 177, 251–255.Google Scholar
Register, TC & Adams, MR (1998) Coronary artery and cultured aortic smooth muscle cells express mRNA for both the classical estrogen receptor and the newly described estrogen receptor beta. Journal of Steroid Biochemistry and Molecular Biology 64, 187–191.Google Scholar
Rice, MM, LaCroix, AZ, Lampe, JW, van Belle, G, Kestin, M, Sumitani, M, Graves, AB, Larson, EB (2001) Dietary soy isoflavone intake in older Japanese American women. Public Health Nutrition 4, 943–952.CrossRefGoogle ScholarPubMed
Ridker, PM, Hennekens, CH, Rifai, N, Buring, JE & Manson, JE (1999) Hormone replacement therapy and increased plasma concentration of C-reactive protein. Circulation 100, 713–716.Google Scholar
Rimbach, G, Weinberg, PD, de Pascual-Teresa, S, Alonso, MG, Ewins, BA, Turner, R, Minihane, AM, Botting, N, Fairley, B, Matsugo, S, Uchida, Y & Cassidy, A (2004) Sulfation of genistein alters its antioxidant properties and its effect on platelet aggregation and monocyte and endothelial function. Biochimica et Biophysica Acta 1670, 229–237.CrossRefGoogle ScholarPubMed
Saijonmaa, O, Nyman, T, Pacek, P & Fyhrquist, F (1998) Oncostatin M regulates endothelin-1 production in human endothelial cells. American Journal of Physiology 275, H662–H667.Google Scholar
Samman, S, Lyons Wall, PM, Chan, GS, Smith, SJ & Petocz, P (1999) The effect of supplementation with isoflavones on plasma lipids and oxidisability of low density lipoprotein in premenopausal women. Atherosclerosis 147, 277–283.Google Scholar
Satake, N & Shibata, S (1999) The potentiating effect of genistein on the relaxation induced by isoproterenol in rat aortic rings. General Pharmacology 33, 221–227.Google Scholar
Shames, BD, Selzman, CH, Pulido, EJ, Meng, X, Meldrum, DR, McIntyre, RC Jr, Harken, AH & Banerjee, A (1999) LPS-induced NF-kappaB activation and TNF alpha release in human monocytes are protein tyrosine kinase dependent and protein kinase C independent. Journal of Surgical Research 83, 69–74.CrossRefGoogle ScholarPubMed
Simoncini, T & Genazzani, AR (2003) Non-genomic actions of sex steroid hormones. European Journal of Endocrinology 148, 281–292.Google Scholar
Simoncini, T, Rabkin, E & Liao, JK (2003) Molecular basis of cell membrane estrogen receptor interaction with phosphatidylinositol 3-kinase in endothelial cells. Arteriosclerosis Thrombosis and Vascular Biology 23, 198–203.Google Scholar
Simons, LA, von Konigsmark, M, Simons, J & Celermajer, DS (2000) Phytoestrogens do not influence lipoprotein levels or endothelial function in healthy, postmenopausal women. American Journal of Cardiology 85, 1297–1301.Google Scholar
Sobey, CG, Weiler, JM, Boujaoude, M & Woodman, OL (2004) Effect of short-term phytoestrogen treatment in male rats on nitric oxide-mediated responses of carotid and cerebral arteries: comparison with 17beta-estradiol. Journal of Pharmacology and Experimental Therapeutics 310, 135–140.Google Scholar
Song, T, Barua, K, Buseman, G & Murphy, PA (1998) Soy isoflavone analysis: quality control and a new internal standard. American Journal of Clinical Nutrition 68, Suppl. 6, 1474S–1479S.Google Scholar
Squadrito, F, Altavilla, D, Crisafulli, A, Saitta, A, Cucinotta, D, Morabito, N, D'Anna, R, Corrado, F, Ruggeri, P, Frisina, N & Squadrito, G (2003) Effect of genistein on endothelial function in postmenopausal women: a randomized, double-blind, controlled study. American Journal of Medicine 114, 470–476.Google Scholar
Squadrito, F, Altavilla, D, Morabito, N, Crisafulli, A, D'Anna, R, Corrado, F, Ruggeri, P, Campo, GM, Calapai, G, Caputi, AP & Squadrito, G (2002) The effect of the phytoestrogen genistein on plasma nitric oxide concentrations, endothelin-1 levels and endothelium dependent vasodilation in postmenopausal women. Atherosclerosis 163, 339–347.Google Scholar
Squadrito, F, Altavilla, D, Squadrito, G, Saitta, A, Cucinotta, D, Minutoli, L, Deodato, B, Ferlito, M, Campo, GM, Bova, A & Caputi, AP (2000) Genistein supplementation and estrogen replacement therapy improve endothelial dysfunction induced by ovariectomy in rats. Cardiovascular Research 45, 454–462.Google Scholar
Sullivan, TR Jr, Karas, RH, Aronovitz, M, Faller, GT, Ziar, JP, Smith, JJ, O'Donnell, TF Jr & Mendelsohn, ME (1995) Estrogen inhibits the response-to-injury in a mouse carotid artery model. Journal of Clinical Investigation 96, 2482–2488.Google Scholar
Teede, HJ, McGrath, BP, DeSilva, L, Cehun, M, Fassoulakis, A & Nestel, PJ (2003) Isoflavones reduce arterial stiffness: a placebo-controlled study in men and postmenopausal women. Arteriosclerosis Thrombosis and Vascular Biology 23, 1066–1071.Google Scholar
Teerlink, T, Neele, SJ, de Jong, S, Netelenbos, JC & Stehouwer, CD (2003) Oestrogen replacement therapy lowers plasma levels of asymmetrical dimethylarginine in healthy postmenopausal women. Clinical Science 105, 67–71.Google Scholar
Thambyrajah, J, Landray, MJ, Jones, HJ, McGlynn, FJ, Wheeler, DC & Townend, JN (2001) A randomized double-blind placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease. Journal of the American College of Cardiology 37, 1858–1863.Google Scholar
Unger, RE, Krump-Konvalinkova, V, Peters, K & Kirkpatrick, CJ (2002) In vitro expression of the endothelial phenotype: comparative study of primary isolated cells and cell lines, including the novel cell line HPMEC-ST1.6R. Microvascular Research 64, 384–397.CrossRefGoogle ScholarPubMed
Valkonen, VP, Paiva, H, Salonen, JT, Lakka, TA, Lehtimaki, T, Laakso, J & Laaksonen, R (2001) Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine. Lancet 358, 2127–2128.Google Scholar
Vallance, P, Leone, A, Calver, A, Collier, J & Moncada, S (1992) Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339, 572–575.Google Scholar
Valsta, LM, Kilkkinen, A, Mazur, W, Nurmi, T, Lampi, AM, Ovaskainen, ML, Korhonen, T, Adlercreutz, H & Pietinen, P (2003) Phyto-oestrogen database of foods and average intake in Finland. British Journal of Nutrition 89, Suppl. 1, S31–S38.Google Scholar
van der Schouw, YT, Pijpe, A, Lebrun, CE, Bots, ML, Peeters, PH, van Staveren, WA, Lamberts, SW & Grobbee, DE (2002) Higher usual dietary intake of phytoestrogens is associated with lower aortic stiffness in postmenopausal women. Arteriosclerosis Thrombosis and Vascular Biology 22, 1316–1322.Google Scholar
van Erp-Baart, MA, Brants, HA, Kiely, M, Mulligan, A, Turrini, A, Sermoneta, C, Kilkkinen, A & Valsta, LM (2003) Isoflavone intake in four different European countries: the VENUS approach. British Journal of Nutrition 89, (Suppl. 1), S25–S30.Google Scholar
Viinikka, L, Orpana, A, Puolakka, J, Pyorala, T & Ylikorkala, O (1997) Different effects of oral and transdermal hormonal replacement on prostacyclin and thromboxane A2. Obstetrics and Gynecology 89, 104–107.Google Scholar
Wagner, AH, Schroeter, MR & Hecker, M (2001) 17Beta-estradiol inhibition of NADPH oxidase expression in human endothelial cells. FASEB Journal 15, 2121–2130.Google Scholar
Wagner, JD, Clarkson, TB, St Clair, RW, Schwenke, DC, Shively, CA & Adams, MR (1991) Estrogen and progesterone replacement therapy reduces low density lipoprotein accumulation in the coronary arteries of surgically postmenopausal cynomolgus monkeys. Journal of Clinical Investigation 88, 1995–2002.Google Scholar
Wagner, OF, Christ, G, Wojta, J, Vierhapper, H, Parzer, S, Nowotny, PJ, Schneider, B, Waldhausl, W & Binder, BR (1992) Polar secretion of endothelin-1 by cultured endothelial cells. Journal of Biological Chemistry 267, 16066–16068.Google Scholar
Walker, HA, Dean, TS, Sanders, TA, Jackson, G, Ritter, JM & Chowienczyk, PJ (2001) The phytoestrogen genistein produces acute nitric oxide-dependent dilation of human forearm vasculature with similar potency to 17beta-estradiol. Circulation 103, 258–262.Google Scholar
Wang, HJ & Murphy, PA (1994) Isoflavone content in commercial soybean foods. Journal of Agricultural and Food Chemistry 42, 1666–1673.Google Scholar
Weatherman, RV & Scanlan, TS (2001) Unique protein determinants of the subtype selective ligand responses of the estrogen receptors (ERalpha and ERbeta) at AP-1 sites. Journal of Biological Chemistry 276, 3827–3832.Google Scholar
Webb, CM, Ghatei, MA, McNeill, JG & Collins, P (2000) 17Beta-estradiol decreases endothelin-1 levels in the coronary circulation of postmenopausal women with coronary artery disease. Circulation 102, 1617–1622.Google Scholar
Weber, C, Negrescu, E, Erl, W, Pietsch, A, Frankenberger, M, Ziegler-Heitbrock, HW, Siess, W & Weber, PC (1995) Inhibitors of protein tyrosine kinase suppress TNF-stimulated induction of endothelial cell adhesion molecules. Journal of Immunology 155, 445–451.Google Scholar
Wei, H, Bowen, R, Cai, Q, Barnes, S & Wang, Y (1995) Antioxidant and antipromotional effects of the soybean isoflavone genistein. Proceedings of the Society for Experimental Biology and Medicine 208, 124–130.Google Scholar
Weitzberg, E, Ahlborg, G & Lundberg, JM (1993) Differences in vascular effects and removal of endothelin-1 in human lung, brain, and skeletal muscle. Clinical Physiology 13, 653–662.Google Scholar
Wheeler-Jones, CP, May, MJ, Morgan, AJ & Pearson, JD (1996) Protein tyrosine kinases regulate agonist-stimulated prostacyclin release but not von Willebrand factor secretion from human umbilical vein endothelial cells. Biochemical Journal 315, 407–416.Google Scholar
Wilcox, JG, Hatch, IE, Gentzschein, E, Stanczyk, FZ & Lobo, RA (1997) Endothelin levels decrease after oral and nonoral estrogen in postmenopausal women with increased cardiovascular risk factors. Fertility and Sterility 67, 273–277.Google Scholar
Wingrove, CS & Stevenson, JC (1997) 17beta-Oestradiol inhibits stimulated endothelin release in human vascular endothelial cells. European Journal of Endocrinology 137, 205–208.Google Scholar
Wojakowski, W & Gminski, J (2001) Soluble ICAM-1, VCAM-1 and E-selectin in children from families with high risk of atherosclerosis. International Journal of Molecular Medicine 7, 181–185.Google Scholar
Woodman, OL & Boujaoude, M (2004) Chronic treatment of male rats with daidzein and 17beta-oestradiol induces the contribution of EDHF to endothelium-dependent relaxation. British Journal of Pharmacology 141, 322–328.Google Scholar
Xu, WH, Zheng, W, Xiang, YB, Ruan, ZX, Cheng, JR, Dai, Q, Gao, YT & Shu, XO (2004 a) Soya food intake and risk of endometrial cancer among Chinese women in Shanghai: population based case-control study. BMJ 328, 1285.Google Scholar
Xu, Y, Armstrong, SJ, Arenas, IA, Pehowich, DJ & Davidge, ST (2004 b) Cardioprotection by chronic estrogen or superoxide dismutase mimetic treatment in the aged female rat. American Journal of Physiology 287, H165–H171.Google Scholar
Yamaguchi, K, Honda, H, Wakisaka, C, Tohei, A & Kogo, H (2001) Effects of phytoestrogens on acetylcholine- and isoprenaline-induced vasodilation in rat aorta. Japanese Journal of Pharmacology 87, 67–73.Google Scholar
Yamamoto, S, Sobue, T, Kobayashi, M, Sasaki, S, Tsugane, S & Japan Public Health Center-Based Prospective Study on Cancer Cardiovascular Diseases Group (2003) Soy, isoflavones, and breast cancer risk in Japan. Journal of the National Cancer Institute 95, 906–913.Google Scholar
Yamamoto, S, Sobue, T, Sasaki, S, Kobayashi, M, Arai, Y, Uehara, M, Adlercreutz, H, Watanabe, S, Takahashi, T, Iitoi, Y, Iwase, Y, Akabane, M & Tsugane, S (2001) Validity and reproducibility of a self-administered food-frequency questionnaire to assess isoflavone intake in a Japanese population in comparison with dietary records and blood and urine isoflavones. Journal of Nutrition 131, 2741–2747.Google Scholar
Yeung, J & Yu, TF (2003) Effects of isoflavones (soy phyto-estrogens) on serum lipids: a meta-analysis of randomized controlled trials. Nutrition Journal 2, 15.Google Scholar
Zeiher, AM, Schachinger, V & Minners, J (1995) Long-term cigarette smoking impairs endothelium-dependent coronary arterial vasodilator function. Circulation 92, 1094–1100.Google Scholar