Estrogen and vascular system: more questions for the future

Gender-specific differences in the incidence of carlocalized in endothelial and vascular smooth muscle cells, diovascular disease were recognized half a century ago [1]. and consequent regulation of gene expression [5]. Indeed, It is now well established that while the risk of heart chronic exposure to estrogen upregulates endothelial NOdisease in men increases constantly with age, presynthase gene expression in vascular endothelium [22,23] menopausal women have a significantly lower risk which, and attenuates phosphoinositide turnover and inositol however, increases rapidly after menopause to levels phosphate production in vascular smooth muscle [24], comparable to that of their male counterparts. In fact, in which may account for the estrogen-induced long-term postmenopausal women receiving estrogen substitution, changes in vascular sensitivity towards neurotransmitters the cardiovascular mortality is 30–50% less than that and humoral factors. found in their untreated female counterparts [2]. Based on In addition to the effects observed following chronic these epidemiological data, it has been suggested that treatment, estrogen has direct and acute effects on vascular estrogen protects against cardiovascular diseases. The tone. It has been reported that estrogen relaxes arteries research related to the mechanism of estrogen actions through both endothelium-independent [25–28] and endoindicated that the cardiovascular protective effects of thelium-dependent mechanism [29–32]. Endothelium-inestrogen are mediated by an anti-atherogenic action on the dependent estrogen-induced vasorelaxation was usually 21 lipid profile and by direct effects on arterial wall [3–5]. In ascribed to the blockade of Ca channels and inhibition 21 this regard, it has been demonstrated that chronic exposure of Ca influx, and to changes in tissue cAMP and cGMP to estrogen reduces neointimal and vascular smooth muscle levels [26,33–36], while the estrogen-induced endoproliferation and remodels arteries both in vitro and in vivo thelium-dependent relaxation was commonly associated [6–10]. In addition, long-term exposure of arteries to with the stimulation of NO production from the vascular estrogen has been proposed to lead to decreased vascular endothelium [29–32]. responsiveness to vasoconstrictors [11–15] on one hand, Therefore, up to now, it was generally accepted that and increased responsiveness to vasodilators on the other estrogen has genomic and non-genomic actions on blood hand [16,17]. It has been proposed that these effects of vessels. Estrogen effects through genomic mechanism is estrogen may be related to estrogen-mediated increase in characterized by the three main features: (1) the biological basal or agonist-stimulated production of endotheliumeffect can be evoked by low, nanomolar, concentrations of derived relaxing factors, such as nitric oxide (NO) [11], estrogen, (2) chronic treatment is necessary for the effect prostacyclin [18,19] or yet unidentified relaxing mediator through genomic mechanism, (3) this effect can be an[20]. Besides its effect on endothelial function, estrogen tagonized by antagonists of estrogen receptors. In contrast, may also alter intracellular signaling pathways in vascular actions of estrogen through non-genomic mechanisms are smooth muscle in such way as to promote the decrease in characterized by: (1) high, micromolar, concentrations are vascular responsiveness to vasoconstrictors [15,21]. It is required for estrogen actions through non-genomic mechabelieved that long-term effects of estrogens on vascular nisms, (2) this type of estrogen effects can be observed wall are mediated through activation of estrogen receptors, immediately following the administration of estrogen, (3) non-genomic effect cannot be antagonized by the antagonist of estrogen receptors. *Corresponding author. Tel.: 11-507-284-4884; fax: 11-507-284In the current issue of Cardiovascular Research, Teoh et 9111. al. [37] demonstrate that short-time exposure to 17 b E-mail address: jovanovic.aleksandar@mayo.edu (A. Jovanovic) See pages 224–231. estradiol, at the low concentrations that have no effect on