Clinical and Experimental Pharmacology and Physiology (2008) 35, 396– 401 doi: 10.1111/j.1440-1681.2008.04885.x Blackwell Publishing Asia Original Articles Estradiol, cytokines and atheroma P Gourdy et al. ROLE OF INFLAMMATORY CYTOKINES IN THE EFFECT OF ESTRADIOL ON ATHEROMA P Gourdy,* B Calippe,* H Laurell,* F Trémollières,* V Douin-Echinard,* F Lenfant,* F Bayard,* JC Guery † and JF Arnal* *Department of Vascular Biology and Atherothrombosis, INSERM U858-I2MR, CHU Toulouse-Rangueil, and † Department of Immunology, INSERM U 563, CHU Toulouse-Purpan, Toulouse, France SUMMARY 1. Although hormonal therapy (HT) may increase the risk of coronary heart disease (CHD) and stroke in postmenopausal women, epidemiological studies (protection in premenopausal women) suggest and experimental studies (prevention of fatty streak development in animals) demonstrate a major athero- protective action of estradiol (E2). The understanding of the deleterious and beneficial effects of oestrogens is thus required. 2. The immuno-inflammatory system plays a key role in the development of fatty streak deposit as well as in the rupture of the atherosclerotic plaque. Although E2 favours an anti-inflammatory effect in vitro (cultured cells), it rather elicits a pro-inflammatory response in vivo involving several subpopulations of the immuno- inflammatory system, which could contribute to plaque desta- bilization. The functional role of several cytokines was explored in hypercholesterolemic mice. The atheroprotective effect of E2 was fully maintained in mice deficient in interferon-g or interleukin-12, as well as IL-10. In contrast, the protective effect of estradiol was abolished and even reversed in hypercholesterolemic mice given a neutralizing anti-transforming growth factor-b (TGF-b) antibody. Endothelium is another important target for E2, since it not only potentiates endothelial nitric oxide and prostacyclin production, but also controls trafficking of the populations of the immuno-inflammatory system. 3. To conclude, the respective actions of oestrogens on the cell populations involved in the pathophysiology of atherothrombosis may be influenced, among others, by the timing of HT initiation, the status of the vessel wall and, as recently demonstrated the status of the TGF-b pathway. Key words: atheroma, atherosclerosis, cardiovascular risk, oestrogens, thrombosis. INTRODUCTION Estrogens play a pivotal role in sexual development and reproduction and are also implicated in a number of physiological processes in various tissues including the cardiovascular system. Epidemiological evidence suggests that oestrogens protect women against coronary heart disease (CHD) before the age of menopause. In addition, decreased CHD risk has been for a long time the main expected benefit of hormone therapy (HT) among postmenopausal women. 1 However, large randomized controlled trials failed to demonstrate a beneficial effect of HT, for both secondary prevention (Heart and Estrogen/Progestin Replacement Study, HERS) 2 and primary pre- vention (Women’s Health Initiative study, WHI). 3 This is in contrast to the large amount of data from experimental models of atherosclerosis, where estradiol (E2) treatment prevents the development of fatty streaks in comparison with castrated animals given a placebo. 4 Besides these beneficial effects, there is clear evidence that oral oestrogens increase the risk of venous thromboembolism (VTE) among postmenopausal women. 3 Thus, the cardiovascular effects of oestrogens are far more complex than initially assumed and depend on the clinical outcomes (endpoints) as well as the sex steroid origin (endogenous versus exogenous) and hormone regimens E2 PREVENTS FATTY STREAK FORMATION IN ALL ANIMAL SPECIES Studies in primates, mainly conducted by Clarkson et al. have pro- vided convincing evidence for the primary prevention of coronary artery atherosclerosis when oestrogens are given soon after the development of oestrogen deficiency. 5 Equally convincing data from studies in cynomolgus monkeys indicate a total loss of the beneficial effects of oestrogens if the treatment is delayed for a period equal to six postmenopausal years for women. 5 Moreover, in the monkey model, an attempt has been made to identify the most effective hormone treatment regimen in preventing the progression of coronary artery atherosclerosis. By far, the most successful approach is that of using oestrogen during the perimenopausal transition, followed directly by hormone replacement therapy postmenopausally. However, only mouse models allow the elucidation of the cellular or molecular mechanisms of E2 action. 4,6,7 Ovariectomy of apolipo- protein E (apoE)-knock out (KO) or low density lipoprotein (LDL) receptor-KO mice is followed by an increase in fatty streak lesion area and exogenous E2 prevents the fatty streak deposit in both models. However, serum E2 concentrations of the order of those encountered during gestation are necessary for maximal protection. 8,9 Correspondence: JF Arnal, INSERM U858-I2MR, Départ Biologie Vasculaire, Equipe 9: Athérothrombose/Estrogènes Batiment L3, 3eme etage, CHU Rangueil, BP 84225, 31432 Toulouse cedex 4, France. Email: arnal@toulouse.inserm.fr Presented at the IVth Franco-Australian Meeting on Hypertension, Northern Territory, Australia, September 2007. The papers in these proceedings have been peer reviewed. Received 13 August 2007; revision 21 November 2007; accepted 25 November 2007. © 2008 The Authors Journal compilation © 2008 Blackwell Publishing Asia Pty Ltd