During their fertile stage, women show a lower incidence of cardiovascular diseases than aged matched men, benefit that disappears after menopause. Although age- and sex-related differences point to sexual hormones as possible cardiovascular protective factors, there is controversy surrounding the clinical use of estradiol as a therapeutic agent for cardiovascular disease in women. Most of the cardiovascular effects of estrogens are attributed to 17β-estradiol (E2), and is related to vascular endothelium functions (Sobrino et al., 2009). 17β-estradiol promotes the release of vasoactive compounds, such as endothelial-derived nitric oxide (NO) through an increased expression and activity of endothelial NO synthase, and prostacyclin and thromboxane A2, through the regulation of cyclooxygenases expression and activity, and also shifts the angiotensin axis towards an angiotensin 1-7 production (Sobrino et al., 2017). Mechanisms underlying estradiol vascular function also include anti-inflammatory and anti-oxidative effects, and epigenetic modifications. Recently, the demonstration of a change in the transcriptomic profile of endothelial cells in response to 17β-estradiol and in particular, the involvement of different miRNA in the regulatory pathways of vascular function, extends our expectations on estrogenic vascular actions (Vidal-Gomez et al., 2018). The wide range of vascular actions mediated by estrogens is mainly exerted by estrogen receptors (ER) through rapid and/or genomic mechanisms. Vascular cells, both endothelial and smooth muscle, express the classic ER, α and β, and also GPER, a G-protein coupled membrane ER. Likewise, a number of ER isoforms have been described so far. In addition, estrogens differently interplay with other sex hormones by modifying the expression of ER and progesterone receptors and by regulating the hormone levels. Therefore, the current cardiovascular approach in women health is to resolve discrepancies between the cardiovascular beneficial profile exhibited by estrogens in experimental and some clinical studies and the large randomized trials that could be explained, at least, by two, non-exclusive evidences (Novella et al., 2012). On the one hand, the “Timing Hypothesis”, which states that estrogen-mediated vascular benefits occur only before the detrimental effects of aging are established in the vasculature. On the other hand, changes in the expression of ER, associated to aging and/or hormone status, that could led to a deleterious balance of ERβ over ERα, generally associated with higher oxidative stress and atherosclerotic plaque formation.