Impact of Dietary Soy Isoflavones in Pregnancy on Fetal Programming of Endothelial Function in Offspring BARBARA BONACASA, 1 RICHARD C.M. SIOW AND GIOVANNI E. MANN Cardiovascular Division, British Heart Foundation Centre of Research Excellence, School of Medicine, King’s College London, London, UK Address for correspondence: Prof. Giovanni E. Mann, Cardiovascular Division, School of Medicine, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK. E-mail: giovanni.mann@kcl.ac.uk 1 Current address: Dpto. Fisiologı ´a, Universidad de Murcia, Murcia, Spain. Received 14 December 2010; accepted 26 January 2011. ABSTRACT Epidemiological evidence suggests that soy-based diets containing phytoestrogens (isoflavones) afford protection against cardio- vascular diseases (CVDs); however, supplementation trials have largely reported only marginal health benefits. The molecular mechanisms by which the isoflavones genistein, daidzein, and equol afford protection against oxidative stress remain to be investigated in large scale clinical trials. Isoflavones are transferred across the placenta in both rodents and humans, yet there is limited information on their actions in pregnancy and the developmental origins of disease. Our studies established that feeding a soy isoflavone-rich diet during pregnancy, weaning, and postweaning affords cardiovascular protection in aged male rats. Notably, rats exposed to a soy isoflavone-deficient diet throughout pregnancy and adult life exhibited increased oxidative stress, diminished antioxidant enzyme and eNOS levels, endothelial dysfunction, and elevated blood pressure in vivo. The beneficial effects of refeeding isoflavones to isoflavone-deficient rats include an increased production of nitric oxide and EDHF, an upregulation of antioxidant defense enzymes and lowering of blood pressure in vivo. This review focuses on the role that isoflavones in the fetal circulation may play during fetal development in affording protection against CVD in the offspring via their ability to activate eNOS, EDHF, and redox-sensitive gene expression. Key words: intrauterine programming, fetal programming, developmental plasticity, isoflavones, genistein, daidzein, equol, endothelial nitric oxide synthase, endothelium-derived hyper- polarizing factor, endothelial function, vascular protection, redox signaling, Nrf2, mitochondria, pregnancy, pre-eclampsia, gestational diabetes, intrauterine growth restriction, epigenetics Abbreviations used: Ach, acetylcholine; AHA, American Heart Association; Akt, protein kinase B; ARE, antioxidant response element; L-Arg, L-arginine; BH4, tetrahydrobiopterin; BVR, biliverdin reductase; cat, catalase; Cav-1, caveolin-1; CM, cardiac myocytes; CO, carbon monoxide; CVD, cardiovascular disease; EDHF, endothelium-derived hyperpolarizing factor; EGFR, epidermal growth factor receptor; EpRE, electrophile response element; ER, estrogen receptor; ERE, estrogen response element; ERK, extracellular signal regulated kinase; eNOS, endothelial nitric oxide synthase; cGMP, cyclic guanosine monophosphate; GCSc, glutamylcysteine synthethase catalytic unit; GPR 30, G-protein- coupled receptor 30; GSH, glutathione; HO-1, heme oxygenase-1; HRT, hormone replacement therapy; Hsp90, heat shock protein 90; i.v., intravenous; Keap1, Kelch-like ECH-associated protein 1; L-NAME, NG-arginine methyl ester; NO, nitric oxide; NOX, NADPH oxidase; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PE, phenylephrine; PI-3K, phosphoinositol 3-kinase; Prx-1, peroxiredoxin-1; ROS, reactive oxygen species; SD, soy protein isoflavone-deficient; SNP, sodium nitroprusside; SP, soy isoflavone-rich diet; SOD, superoxide dismutase; xCT, cystine– glutamate anionic amino acid transporter Please cite this paper as: Bonacasa, Siow and Mann (2011). Impact of Dietary Soy Isoflavones in Pregnancy on Fetal Programming of Endothelial Function in Offspring. Microcirculation 18(4), 270–285. DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE The fetal or developmental origins of CVD were originally described by Barker et al. [8,9,12,13], who postulated that environmental factors in early life, in particular perturba- tions in the intrauterine environment, program the risks for cardiovascular and metabolic disease in adulthood. These programmed changes in functional adaptive responses in utero may underlie the origins of a number of diseases in later life, including coronary heart disease and related disorders such as stroke, hypertension, and type 2 diabetes [5,57]. Although the mechanisms that impair fetal development and program adult CVD remain to be defined, there is accumulating evidence highlighting the importance of fetal adaptations invoked when DOI:10.1111/j.1549-8719.2011.00088.x Invited Review 270 ª 2011 John Wiley & Sons Ltd, Microcirculation, 18, 270–285