The role of estrogen receptors in cardiovascular function

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Estrogens are a family of hormones that have complex effects on the heart. Part of the complexity can be attributed to the presence of 3 estrogen receptors (ER) (ER-alpha, ER-beta, and GPR30). In some cases the activation of these receptors can produce opposing functional effects. Historically the impact of estrogens on the heart have been attributed to changes in gene expression, but more recently rapid, non-genomic effects of ER activation have been reported. We were the first to show that ER-alpha activation changes heart function in <5 min. The objectives of our program are to determine how each ER affects heart function and to identify the intracellular mechanisms.Heart function differs between sexes. Most studies report no differences in ER expression in the heart, but it is unknown if the activation of cardiac ER produces similar functional effects in each sex. Studies examining the physiological effects of estrogens on the heart tend to use only one sex and investigate genomic changes. Our first objective is to determine how male and female mice respond to acute ER activation, and identify the intracellular mechanisms. We will assess heart function following acute ER activation in both sexes, and investigate the molecular changes. These studies will provide insight into sex differences in ER physiology.Females of many mammalian species experience a natural decline in estrogen production by the ovaries at older ages. In humans this results in menopause. Menopause occurs after a transition through the low estrogen producing phase peri-menopause'. The loss of estrogens later in life are proposed to contribute to the ageing of the heart, but how the heart changes during the transition into menopause and how it continues to change following menopause is not clear. Our second objective is to determine how the heart is altered during the peri- and post-menopausal periods, and how the response to acute ER activation is affected.Phytoestrogens are plant-based compounds that are increasingly prevalent in diets. Up to 25% of human infants are fed soy based formula that is rich in phytoestrogens, and many pet foods are supplemented with soy products. The majority of the world's soybean crops are processed and used as feed for food animals. Despite widespread and increasing consumption of phytoestrogens by several animal species, little is known about the effects of these compounds on cardiac physiology, or their mechanisms of action. The effects of phytoestrogens can be opposite to that of animal estrogens, suggesting distinct mechanisms of action. We showed that dietary phytoestrogens reverse the effects of estrogen loss in mice, but no one has examined the physiological effects on the heart in intact female or males. Our third objective is to investigate the impact of dietary phytoestrogens on whole heart function by echocardiography and cardiac catheterization, and to identify intracellular mechanisms.