Role of miRNA in the Regulatory Mechanisms of Estrogens in Cardiovascular Ageing

Pérez-Cremades, Daniel; Mompeón, Ana; Vidal-Gómez, Xavier; Hermenegildo, Carlos; Novella, Susana

doi:https://doi.org/10.1155/2018/6082387

Oxidative Medicine and Cellular Longevity

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Regulatory Mechanisms of Estrogen on Vascular Ageing

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Review Article | Open Access

Volume 2018 | Article ID 6082387 | https://doi.org/10.1155/2018/6082387

Role of miRNA in the Regulatory Mechanisms of Estrogens in Cardiovascular Ageing

Daniel Pérez-Cremades,¹Ana Mompeón,¹Xavier Vidal-Gómez,¹Carlos Hermenegildo,¹and Susana Novella¹

Academic Editor: Ji C. Bihl

Received07 Sept 2018

Accepted13 Nov 2018

Published20 Dec 2018

Abstract

Cardiovascular diseases are a worldwide health problem and are the leading cause of mortality in developed countries. Together with experimental data, the lower incidence of cardiovascular diseases in women than in men of reproductive age points to the influence of sex hormones at the cardiovascular level and suggests that estrogens play a protective role against cardiovascular disease and that this role is also modified by ageing. Estrogens affect cardiovascular function via their specific estrogen receptors to trigger gene expression changes at the transcriptional level. In addition, emerging studies have proposed a role for microRNAs in the vascular effects mediated by estrogens. miRNAs regulate gene expression by repressing translational processes and have been estimated to be involved in the regulation of approximately 30% of all protein-coding genes in mammals. In this review, we highlight the current knowledge of the role of estrogen-sensitive miRNAs, and their influence in regulating vascular ageing.

1. Introduction

The prevalence, incidence, and prognosis of cardiovascular diseases differ between genders. Indeed, statistical data reveal that women develop cardiovascular disease later than men [1] and the incidence of cardiovascular diseases in women increases from menopause [2, 3]. Both clinical and experimental data have extensively demonstrated the beneficial effects of estrogens at the cardiovascular level [4, 5], although hormonal replacement therapies (HRTs) in postmenopausal women have been implemented with controversial results [6, 7]. Such studies have led some researchers to conclude that the protective effect of HRT depends on age [8].

Ageing is a physiological and multifactorial process characterized by the progressive loss of anatomical and functional integrity, which leads to an increased risk of different pathologies, including cardiovascular disease. At the molecular level, different mechanisms have been established as crucial in the regulation of the ageing process [9]. Among these, epigenetic mechanisms affect gene expression without causing changes in the DNA sequence and can be influenced by external factors, including the environment and lifestyle [10].

Some evidence indicates that estrogen-dependent regulation of cardiovascular function in ageing is mediated by epigenetic mechanisms. An age-related increase in methylation-associated inactivation of genes encoding estrogen receptors (ERs) has been described, and ER methylation in atherosclerotic plaques is higher than in nonplaque regions in vascular tissues [11, 12], which suggests that estrogen activity in atherogenesis and vascular system aging is epigenetically regulated. Another epigenetic mechanism that has also been associated with estrogens is histone modification. In this regard, in a postmenopausal metabolic syndrome murine model, estradiol prevented cardiovascular dysfunction by suppressing histone H3 acetylation [13].

In addition to DNA methylation and histone modification, the most recently described epigenetic mechanism is RNA-based machinery. Regulatory noncoding RNAs are classified depending on RNA length, and among them, microRNAs (miRNAs) constitute the dominant class in most tissues. MiRNAs regulate protein translation by targeting their target messenger RNAs (mRNAs) via sequence-specific interaction to repress translation or degrade target mRNA [14]. In addition, emerging evidence suggests that miRNAs have also nuclear functions in the regulation of gene expression at transcriptional level [15]. Most miRNAs are located within cells, although some have also been found circulating in body fluids [16]. Thus, miRNA-mediated regulation is now considered one of the most important posttranscriptional gene regulation mechanisms and is estimated to modulate up to 30% of mammal genes, including important roles in human physiology, ageing, and cardiovascular function [17, 18].

Given the world’s increasingly ageing population [19] and that cardiovascular diseases are the leading cause of death in developed countries, it is important to improve our understanding of the regulatory mechanisms underlying the ageing of the cardiovascular system. In addition, although growing evidence has established miRNAs as crucial epigenetic regulators of vascular function, their role in the regulation of estrogen in cardiovascular ageing has not yet been fully elucidated. Therefore, in this review, we summarize current knowledge of the role of estrogens in cardiovascular function and ageing with a special focus on the miRNAs related to estrogens during female vascular ageing.

2. The Involvement of Estrogens in Vascular Function

Estrogens modulate the cardiovascular system directly by acting on vascular and inflammatory cells, which express ERs, or indirectly via systemic effects [20]; estrogen functions through ERs by genomic and nongenomic mechanisms. In the former, also known as the “classical” mechanism, estrogens bind to ERs to form a complex that regulates gene transcription by binding to specific DNA motifs in gene promoter regions [21]. In this sense, ERα and ERβ are the two main ER isoforms, and these form homo- or heterodimers, which can induce changes in gene expression. The involvement of specific ER isoforms in estrogen-mediated effects has been extensively studied [22], and both opposing gene expression regulatory effects [23, 24] and redundant mediatory roles [25, 26] have been described. Estrogen signaling is selectively regulated by the relative balance between ERα and ERβ expression in target organs [27], although the beneficial effects that estrogens have on the vascular system are mainly attributed to ERα [28, 29]. Furthermore, estrogens can also trigger fast responses through plasma membrane ER receptors and G protein-coupled ERs (GPERs) [30].

In general, the vascular protective effects of estrogens are attributed to their role in increasing arterial vasodilation, their action on vasoactive mediator release and smooth muscle contraction, inhibition of inflammatory processes, and regulation of systemic lipid metabolism and oxidative stress balance [2, 31, 32]. The regulation of vascular reactivity by estrogens is mainly related to the maintenance of normal endothelial function [33]. In endothelial cells, estrogens modulate nitric oxide (NO) bioavailability by both genomic and nongenomic effects by increasing endothelial NO synthase (eNOS) expression at the transcriptional level, eNOS activation through phosphorylation, and regulation of its endogenous inhibitors and cellular location [34–36]. Moreover, a role for estrogens in regulating other vascular mediators related to prostanoids and endothelin signaling has also been described. Estradiol increases prostacyclin release by upregulating cyclooxygenase 1 (COX-1) and prostacyclin synthase (PGIS) expression in endothelial cells [37] and by decreasing endothelin-1 release in both basal and stimulated conditions [38, 39].

In addition to the regulation of endothelial-derived factors, estrogens directly regulate the smooth muscle layer by inhibiting the proliferation, migration, and vascular contraction of vascular smooth muscle cells (VSMCs) [40]. Indeed, estrogen-mediated vasorelaxation can also occur in endothelium-denuded segments [41]. Specifically, estradiol decreases smooth muscle constriction by interfering in the mechanisms of Ca²⁺ mobilization and Ca²⁺ entry [42] and by activating K⁺ channels [43], leading to membrane hyperpolarization and vascular relaxation. Estrogen can also modulate vasoconstriction by interfering in protein kinase C and Rho-kinase signaling in VSMCs [44, 45].

The renin-angiotensin system (RAS) is another important regulator of vascular contractibility which is regulated by estrogen. Estrogens are implicated in the inhibition of circulating renin, the activity of angiotensin-converting enzymes, and in circulating angiotensin (Ang) II levels [46]. Furthermore, components of RAS are synthesized and act locally in different tissues, including in the vasculature. In this case, estradiol increases the expression of Ang 1–7 by inducing the expression of angiotensin-converting enzymes [47] and of Ang II receptor type 1 expression [48] in endothelial cells, thus promoting vasodilation. In addition, estradiol-dependent NO production is mediated by Ang 1–7-induced activation of the Mas receptor [49], suggesting the presence of a functional interaction between both these pathways.

The beneficial effects of estrogens in the cardiovascular system are also attributed to their role in modulating the inflammatory response [50] and vascular lipid accumulation [32]. Estrogens inhibit monocyte-endothelial interactions by reducing the expression of cell adhesion molecules in the endothelium when exposed to inflammatory stimuli [51, 52]. Moreover, a reduction in neutrophil chemotaxis [53] and leukocyte infiltration [54] have been established as inflammatory regulatory mechanisms which are mediated by estrogens after vascular injury. Estradiol also reduces the expression of superoxide-induced adhesion molecules and cytokines in VSMCs by inhibiting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression [55]. Moreover, it regulates oxidative stress by decreasing both the expression and activity of superoxide dismutase in VSMCs [56] and endothelial cells [57]. Estrogens can also confer protective effects by modulating systemic lipid metabolism [32], lipid-vascular wall interactions by reducing lipid loading [58, 59], and oxidative stress-mediated LDL modifications [60], thus preventing the formation of foam cells.

3. The Role of Estrogens in Vascular Ageing

Epidemiological data reveal sex differences in the number of deaths caused by cardiovascular disease. These numbers are greater in men than in women under the age of 65 and similar over this age [61], suggesting the importance of ageing in sex-related differences observed in cardiovascular disease. In this regard, sex-specific differences of cardiovascular ageing have been reported, and these patterns have been explained by both hormonal and nonhormonal factors [62].

Considering the beneficial role of estrogens in the cardiovascular systems described above, the use of HRT in postmenopausal women has produced controversial results [6, 7]. The current consensus indicates that the protective effects that estrogens confer on cardiovascular function depend on the prompt initiation of estrogen therapy after menopause [63]. The phenomenon is referred to as the “timing hypothesis” and postulates that estrogen supplementation may only have beneficial effects when initiated before the detrimental effects that ageing has on the cardiovascular system become established [8]. Vascular ageing is associated with endothelial dysfunction and arterial stiffening, vascular remodeling, and increased inflammation [64]. These characteristics can lead to pathological conditions such as myocardial hypertrophy, fibrotic tissue formation, and increased systolic pressure, resulting in a higher risk of atherosclerosis, hypertension, and ischemic cardiovascular disease [65]. Endothelial dysfunction is less prominent in premenopausal women compared to age-matched men and postmenopausal women, which highlights the protective effect of estrogens [66]. Indeed, in a recent study, Nicholson et al. demonstrated that the contractility responses of uterine arteries to estradiol treatment in postmenopausal women were impaired compared to their premenopausal counterparts [67].

The vascular ageing process is associated with a decline in endothelial-dependent relaxation and an increased vasoconstrictor responses mediated by an imbalance between vasodilator and vasoconstriction factors [68–70]. In this regard, NO and prostanoids seem to be the main pathways implicated, and these act by progressively reducing the bioavailability of NO and increasing vasoconstrictor prostanoids in aged vascular tissues. Indeed, relaxation induced by bradykinin in isolated mesenteric microvessels was mainly mediated by the action of NO, although COX-dependent vasodilators were also implicated in young subjects, whereas COX-dependent activity produced vasoconstriction in older subjects [69]. Although some of the data regarding eNOS expression at the molecular level are contradictory, ageing progressively decreases eNOS activity both in animal models and in human samples [71, 72]. Moreover, decreased expression of the eNOS cofactor, tetrahydrobiopterin [73], elevated circulating levels of endogenous inhibitors [74], and enhanced oxidative stress [69] have also been postulated as mechanisms which underlie decreased eNOS activity during ageing. Conversely, rather than altered expression of the COX isoforms, an age-associated switch from vasodilatory to vasoconstrictor prostanoid release has been related to enhanced expression of the thromboxane A2 (TXA2) receptor in the smooth muscle layer in both human mesenteric arteries and in aortic segments from female mice [69, 70, 75].

Oxidative stress is also increased in aged tissues, including the vascular system, and influences endothelial dysfunction by scavenging NO, thus decreasing its bioavailability [76]. Increased oxidative stress levels in vascular ageing are caused by altered antioxidant enzyme expression and enhanced production of reactive oxygen species (ROS) mainly by mitochondria and NADPH oxidase but also by COX and uncoupled eNOS [77]. The role of estrogens in oxidative stress during ageing has been previously reported: in vascular tissues, a decline in NO-mediated vasodilation is associated with increased ROS, especially superoxide, in coronary arterioles [78]. In the same study, the authors describe a decrease in Cu/Zn superoxide dismutase expression in both aged and ovariectomized rats, while estrogen replacement restores its expression to the levels of young intact animals [78]. Furthermore, COX-dependent superoxide production induced by a TXA2 analogue in female aortic segments was enhanced by ageing and estrogen deprivation, findings that were abrogated by estrogen supplementation [79].

Ageing also influences the structural properties of vasculature, and changes in the media thickness and extracellular fiber content contribute to low arterial compliance. Specifically, ageing is associated with the increased production of collagen fibers and decreased elastin fiber synthesis, vascular calcification, and VSMC proliferation [80]. Estrogen administration mitigates progressive age-dependent reductions both in human carotid artery wall thickness in postmenopausal women [81] and in the mesenteric arteries of old female rats [82]. In addition, increased collagen content has been associated with decreased activity and protein levels of specific collagen-degrading metalloproteinase enzymes [82, 83]. Finally, aberrant VSMC growth is also associated with ageing-associated remodeling processes as VSMCs switch from a contractile to synthetic-proliferative phenotype [84]. As previously described, estrogens inhibit the proliferation of cultured VSMCs [40] and it is thought that ageing males are more prone than females to these changes in the VSMC phenotype [85]. In addition, estrogen treatment also attenuates neointimal formation after vascular damage [86]. Finally, in relation to these metalloproteinase and VSMC phenotypes, estrogens may be involved in plaque instability and thus the greater cardiovascular disease risk in postmenopausal women who start HRT late.

Along with endothelial dysfunction and vascular remodeling, the other key player in vascular ageing is inflammation. Ageing is associated to a progressive increment of the tissue’s proinflammatory status, phenomenon termed as “inflammageing.” The signaling of this low-grade chronic inflammation state is linked to an increased cell death, a metabolic dysfunction and a proteostasis loss, and it is also associated with an age-related functional detriment [87]. At vascular level, the ageing process is characterized by an acquisition of a proinflammatory phenotype with increased release of cytokines and enhanced cell adhesion molecules expression, developing a more adhesive endothelium, phenomenon also known as endothelial activation [64, 88]. The role of estrogens as an anti- and/or proinflammatory factor in this process is controversial and may be dependent on immune stimuli, the cell types involved in the response, organ target, timing and concentration of their administration, intracellular metabolism of estrogen, and relative expression of the implicated ERs [50]. In a study using uterine arteries from postmenopausal women that were exposed to estradiol, Novella et al. demonstrated that although estradiol exposure decreased most of the inflammatory cytokines assessed in women in the early stages of menopause, ageing was associated with estrogen’s effect on the switch from anti-inflammatory to proinflammatory in the arteries of women who had started menopause at least 10 years prior [89], suggesting that the effect of estrogens is timing-dependent. In addition, estradiol attenuates inflammatory responses in macrophages and VSMCs derived from young but not old female mice [90], suggesting that the anti-inflammatory properties of estradiol are lost as ageing continues.

As mentioned above, the relative expression of specific ERs has been related to the role of estrogens in vascular ageing and it has postulated that a change in the balance between ERα and ERβ could explain the lack of vascular protection provided by estrogen. In that sense, an age-dependent increase in ERβ but not in ERα expression was observed in uterine arteries from postmenopausal women [89], thus producing this increased ERβ/ERα ratio. In young ovariectomized mice, although estrogen supplementation downregulated ERs, it did not alter the ERβ/ERα ratio in endothelium or smooth muscle; in contrast, the ERβ/ERα ratio increased after estrogen treatment in aged female mice [91]. Finally, decreased ERα expression was also reported in aged compared to young macrophages [90].

4. Sex and Age Influence in miRNA Expression

Sex and age differences in miRNA expression profiles have been described in different tissues [92–94], providing evidence for the role of sex hormones and ageing in miRNA regulation. Sex differences are usually attributed to the modulation of estrogen transcriptional activity mediated by ERs, and so differences in the miRNA profiles obtained from ER+ and ER− breast cancer cells [95, 96] are related to the loss of ER binding sites located near the miRNA sequences which are found less abundance in ER− breast cancer cells [96]. At the vascular cell level, ER binding sites were located within the regulatory region of estradiol-regulated miRNAs [97, 98].

Sex-biased miRNAs are also driven by the expression of miRNAs located in sex chromosomes. It is worth noting that, according to miRBase (March 2018; http://www.mirbase.org), 118 miRNAs are located on the human X chromosome but only 4 were present on the Y chromosome. Most X chromosome miRNAs escape X chromosome inactivation which occurs early in development to compensate for gene dosage imbalances between the sexes [99]. In this respect, the mosaicism resulting from X chromosome inactivation may be involved in some of the increased susceptibility to inflammatory and autoimmune diseases experienced by women [100]. Regarding X-linked miRNAs and cardiovascular diseases, Florijn et al. recently reviewed the implication of miRNAs in women with heart failure with a preserved ejection fraction and concluded that estradiol-induced miRNAs are protective while X-linked miRNAs are associated with deleterious effects [101]. Furthermore, both age and estrogens can modulate miRNA profiles by regulating miRNA biosynthesis pathways.

miRNA production is a two-step process involving nuclear cropping and cytosolic dicing; mature miRNAs are derived from a stem-loop transcript (also known as pri-miRNA) which is cleaved in the nucleus by a microprocessor complex—comprising the RNase III, Drosha, and DiGeorge syndrome critical region 8 (DGCR8)—into a small hairpin-shaped RNA (pre-miRNA) which is transported to the cytoplasm through exportin 5 where maturation can be completed. In a second processing step, the pre-miRNA is cleaved—by the RNase III, Dicer—into approximately 22-nt miRNA duplexes. One strand from the miRNA duplex usually remains as a mature miRNA, while the other is generally selectively degraded via a thermodynamic stability-dependent process. Finally, mature miRNAs are loaded into Argonaute (AGO) proteins to form, along with other components, the RNA-induced silencing complex (RISC) effector. The final miRNAs function as a guide by base pairing—usually at the 3-untranslated region (UTR)—to target mRNAs, and AGO proteins recruit factors that induce the translational repression of these mRNAs [102].

With ageing, molecules implicated in miRNA expression machinery become downregulated, thus suggesting that miRNA expression is age-dependent: an effect described in old versus young peripheral blood mononuclear cells [103]. The same study showed that the expression of miRNA biogenesis molecules is depressed in octogenarians compared with centenarians, which may indicate that greater expression of miRNA production components is associated with extraordinarily successful ageing. At the vascular level, Dicer1 is downregulated in old versus young cerebral vessels isolated from rats, which these authors associated with altered miRNA expression profiles and impaired endothelial function [104]. Indeed, the impaired vascular formation observed in Dicer1 knockout mice was one of the first pieces of evidence that related miRNA biosynthesis to vascular function [105]. In endothelial cells, Dicer1 depletion revealed that miRNA processing is essential for correct endothelial gene expression and function, including proliferation and angiogenesis [106, 107].

The role of estrogen in regulating key miRNA production molecules has been reviewed elsewhere [108], and of note, most studies relating estrogen activity and miRNA biosynthesis have been performed in reproductive organs. Differences in key miRNA-processing genes have been observed between ER+ and ER− breast cancer cells [95, 109]; specifically, the expression of Dicer1, DGCR8, and Drosha was higher, and that of Ago-2 was lower in ER+ breast tumors [110]. Nevertheless, among the miRNA processing genes, only Dicer1 contains an ERα binding site in its regulatory region [110]. Furthermore, a regulatory ER-Drosha interaction has been reported in breast cancer cells [111] and an estrogen-dependent increase in exportin-5 expression was reported in the mouse uteri [112]. At the vascular level, global transcriptomic analysis data of endothelial cells treated with estradiol reported the deregulation of key miRNA biosynthesis pathway genes [113]. Specifically, DGCR8 upregulation and Dicer1 and Ago-2 downregulation were observed in estradiol-treated cells, suggesting that estrogens regulate endothelial miRNA production machinery [113].

5. Estrogen-Regulated miRNAs and Vascular Ageing

As described above, sex- and age-specific miRNA profiles are the result of transcriptomic changes, sex chromosome expression, and miRNA biosynthesis regulation. In addition, findings in women receiving HRT have provided insights into the roles of estrogen-associated miRNAs during ageing in different tissues (Table 1). Changes in the miRNA expression profile in bone tissue from both ovariectomy-induced osteoporotic mice and postmenopausal women have been described [114, 115]. Specifically, miR-127 and miR-136 have been described as negative regulators of bone mass [114], whereas the expression level of miR-30b-5p has been proposed as a suitable serum biomarker for osteoporosis and osteopenia in postmenopausal women [115]. Furthermore, Olivieri et al. reported that estrogen has a positive impact in postmenopausal women using HRT as a result of skeletal muscle changes mediated via the suppression of miR-182 and miR-223 expression. These miRNAs are implicated in regulating the insulin/insulin-like growth factor (IGF-1) pathway which is key in muscle mass homeostasis [116]. Moreover, changes in the miRNA expression profile in adipose tissue have recently been described in association with HRT [117]. Specifically, miR-19a-3p was identified as being HRT-sensitive in adipose tissue because its levels in HRT-treated postmenopausal women were similar to those observed in premenopausal women and were higher than in postmenopausal women who did not use HRT. ESR1 is a miR-19a-3p target [118] and, thus, could be involved in the changes in ERα observed in adipose tissue during ageing [119] and may underlie the adverse age-related alterations in adipose metabolism in women [120].

In addition to tissue-specific miRNA expression, estrogen-dependent regulation in circulating miRNAs has also been described both in ovariectomized animals [115] and postmenopausal women receiving HRT [121, 122]. The studies in women were performed in monozygotic twin pairs and showed an association between changes in serum inflammatory markers and inflammatory-related miR-21 and miR-146a [121]. There were also alterations in the miRNAs included in exosomes in postmenopausal women using HRT [122], suggesting that changes in circulating miRNAs are associated with estradiol levels. Therefore, estrogen-sensitive miRNAs could be used both as therapeutic targets and as potential biomarkers for characteristic physiological alterations related to female ageing, such as osteoporosis, sarcopenia, changes in body fat homeostasis, and ageing-associated inflammation.

Specific miRNAs implicated in cardiac and vascular ageing have been reviewed in depth elsewhere [17, 18]. In addition, we have addressed the role of estrogen-regulated miRNAs in cardiovascular function in a recent review [113]. However, how miRNAs are implicated in the action of estrogen in the vasculature during ageing remains to be elucidated. In the following paragraphs, we describe the involvement of specific miRNAs in the effect of estrogens during female vascular ageing, and Tables 2 and 3 summarize the main circulating and tissue-specific miRNAs involved in female vascular ageing, respectively.

miR-126 is highly expressed in vascularized tissues and was the first miRNA reported as being crucial in endothelial biology. It is located within an intron of the epidermal growth factor-like domain multiple 7 (EGFL7) gene which is mostly expressed in endothelium and is involved in vascular angiogenesis. This miR-126 is involved in vascular integrity and angiogenesis [123, 124] but also appears to modulate immune cell adhesion and VSMC function [125, 126]. Serum levels of estradiol are positively associated with miR-126-3p expression throughout the menstrual cycle; estradiol also increases miR-126-3p expression in cultured endothelial cells [127] but decreases it in lymphocytes [128], suggesting that it has a cell-specific effect on miR-126-3p expression. In endothelial cells, estradiol-dependent miR-126-3p suppresses the miR-126-3p targets, Spred1 and VCAM1, and is related to an increase in cell migration, proliferation, and tube formation, while decreases monocyte adhesion [127]. Moreover, miR-126-3p is also implicated in the estradiol-dependent reduction of plaque size in ApoE^−/− mice [127]. Indeed, miR-126 released by endothelial cells controls VSMC behavior [126] and limits neointimal formation [129]. Given that circulating miR-126 expression is altered in several cardiovascular diseases [130], these findings suggest that estradiol’s vasculoprotective and antiatherogenic properties could be partly mediated by miR-126. Circulating miR-126 is downregulated in different cardiovascular diseases [131, 132], although its relationship with and ageing is contradictory; compared to young individuals, miR-126 was downregulated in blood samples from centenarians [133], but miR-126-5p expression in circulating exosomes was higher in postmenopausal versus premenopausal women [122] and miR-126-3p was increased in senescent endothelial cells in vitro and in plasma collected from healthy older patients [134]. Olivieri et al. hypothesize that this miR-126 upregulation is a compensatory mechanism to reduce cell dysfunction during normal ageing.

miR-106 expression is sex-specific. miR-106a/b were among the sex-specific miRNAs regulated via ERβ in a murine model of pressure overload-induced cardiac fibrosis mediated by regulation of specific profibrotic MAPK signaling repressors [135], evidence that miR-106 may be involved in sex-related differences in this pathology. In estradiol-treated rat cardiac fibroblasts, miR-106b expression is decreased in both female and male cells while miR-106a expression is downregulated in female cells but upregulated in male cells [135]; furthermore, miR-106b was downregulated in cultured VSMCs treated with estradiol [97], suggesting that estradiol has sex-specific effects in downregulating miR-106b. In contrast, miR-106b-5p expression was lower in postmenopausal women not using HRT compared to those that did use HRT [122], suggesting that estrogens have the opposite effect on miR-106 expression during ageing. The downregulation of miR-106a has been also reported in replicative endothelial cell ageing [136] and in serum from older women [137]. In endothelial cells treated with tumor necrosis factor alpha (TNF-α), miR-106b-5p exerts antiapoptotic effects by repressing phosphatase and tensin homolog (PTEN) caspase activity [138], and in a rat cardiomyoblast cell line exposed to hypoxia, it suppresses apoptosis by directly targeting p21 [139], findings that concur with the known repressive effects of estrogens on PTEN and apoptosis [140, 141].

In miR-221/222, the cluster containing the miR-221/222 gene is located on the X chromosome and is regulated both by ageing and estrogen-mediated mechanisms; serum levels of miR-222 increase with ageing in both males and females [137]. Moreover, in human aortic endothelial cells, miR-221/222 expression was upregulated in an in vitro replicative senescence model and correlated with decreased eNOS expression and activity [142]. Moreover, endothelial cells transfected with miR-221 and miR-222 showed reduced eNOS protein levels [106]. However, eNOS 3-UTR mRNA does not contain a target sequence for miR-221 or miR-222, suggesting that an intermediate mechanism may be responsible for this miR-221/222-mediated eNOS repression. Indeed, miR-222, that was among the sex-dimorphic miRNAs identified in mice heart tissues and isolated cardiomyocytes, inhibits eNOS expression by directly targeting ets-1 mRNA [143], an upstream eNOS regulator. These results indicate that miR-222 plays an important role in heart function that may be sex-specific in terms of providing female cardioprotection [144]. Conversely, miR-221/222 regulate and are regulated by ERα activity [145], suggesting the presence of a negative regulatory loop between them. One hypothesis is that before menopause, estrogen-ERα activity limits miR-221/222 levels, thus maintaining eNOS expression and cardioprotection. However, ageing and menopause increase miR-221/222 levels and decrease ERα and eNOS expression by downregulating ets-1. In addition, miR-221/222 are strongly upregulated in the carotid artery in a balloon injury model and their depletion suppresses VSMC proliferation and neointimal formation [146] which may explain the role of estrogens in attenuating vascular damage [86].

miR-143/145 activity appears to be essential in regulating VSMCs to prevent the ageing-related switch from a contractile to synthetic-proliferative VSMC phenotype [147], and miR-143/145 dysregulation has been described in different cardiovascular pathologies. These miRNAs maintain VSMCs in a quiescent state and inhibit proliferation by regulating several targets, including angiotensin-converting enzyme [148] which modulates vascular contractibility. It has been reported that miR-143/145 are delivered from endothelial cells to VSMCs where they repress genes associated with dedifferentiation [149] such as myocardin, ELK1, and KLF4. Estradiol induces miR-143/145 expression in pulmonary artery smooth muscle cells (PASMCs) via specific ER binding sites located in their promoter regions [150]. Moreover, estradiol-treated PASMCs secrete exosomes enriched in miR-143/145 which regulate VSMC-endothelium crosstalk in pulmonary arterial hypertension, regulating vascular remodeling [150] and perhaps playing a role in exerting estrogen-mediated effects on the VSMC phenotype. Although no specific studies on miR-143/145 expression in cardiovascular cells during ageing have been undertaken, miR-145 expression negatively correlates with age in patients with coronary artery disease [151].

miR-30 is estrogen-sensitive and its expression is related to estrogen levels in different tissues [110, 152, 153]; indeed, ER binding sites have been identified upstream of the miR-30 transcription start site [96, 98]. Reinforcing the role of estrogens in regulating miR-30b-5p, its expression was downregulated in serum from ovariectomized rats and from postmenopausal osteoporotic women [115] and miR-30b-5p was the most upregulated miRNA in endothelial cells treated with estradiol [98]. There is also evidence that miR-30b family members are involved in cardiovascular diseases because their expression is decreased in vascular injury [154], inversely correlates with blood pressure parameters [155], and inhibits VSMC proliferation and neointimal formation [154]. However, the role of miR-30 family members in myocardial infarction remains controversial [156–158]. In endothelial cells, miR-30 is implicated in angiogenic processes [159], has anti-inflammatory effects by decreasing angiopoietin 2-induced VCAM1 expression [160], and inhibits apoptosis in human coronary artery endothelial cells [161]. In this regard, it is noteworthy that estradiol also has proangiogenic, anti-inflammatory, and antiapoptotic properties in response to vascular injury [162].

miR-23a belongs to the miR-23-24-27 cluster which has been implicated in angiogenic processes and cardiac function [163] and also has ERα binding sites in its regulatory regions. Members of this cluster are upregulated during endothelial replicative ageing [164], and miR-23a overexpression reduces telomere length and induces senescence in human fibroblasts [165]. In serum and myocardium in rats, miR-23a expression inversely correlates with estradiol levels and regulated connexin-43 in a menopausal rat model [166]. In postmenopausal rats, estrogen supplementation rescued blockage of cardiac conduction by decreasing miR-23a, thus revealing potential mechanisms involved in postmenopause-related arrhythmias [167]. Moreover, miR-23a may affect cardiac hypertrophic processes [168]: its increased expression in estrogen-deficient ovariectomized mice causes mitochondrial compromise and ventricular remodeling by directly repressing peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) expression in cardiomyocytes [169]. Moreover, miR-27 is upregulated in senescent endothelial cells [164] and in circulating exosomes in premenopausal versus postmenopausal women [122]. This miRNA has been implicated in LDLR expression [170], angiogenic processes [107], and may be a biomarker for progression in asymptomatic carotid stenosis [171].

miR-203 is upregulated in estradiol-treated mouse aortic VSMCs [97]; miR-203 induction is regulated through an ERα-dependent mechanism and its inhibition abolishes estradiol-mediated inhibition of VSMC proliferation, suggesting a role for miR-203 in the antiproliferative effect of estrogens [97]. In addition, miR-203 can downregulate ERα by direct targeting [172], suggesting its involvement in a regulatory loop. Conversely, increased miR-203 expression found in aged aorta has recently been associated with age-related VSMC stiffness [173].

In miR-144, circulating estradiol concentrations were positively correlated with miR-144-5p in a study of women receiving HRT [122], and in the same study, miR-144-5p was inversely correlated with TNF-α levels, together suggesting it has an estrogen-mediated role in regulating inflammatory processes. Indeed, miR-144 is implicated in targeting superoxide-related proteins such as COX-2 [174] and the NADPH oxidase component Rac1 [175]. Conversely, miR-144 is upregulated in cerebral microvascular endothelial cells from aged mice, and its inhibition upregulates the antioxidant transcription factor NRF2 [176]; miR-144 is also involved in lipid metabolism by repressing the expression of cholesterol efflux regulatory protein ABCA1 [177], while the ABCA1 inducer, nuclear factor LXR, increases miR-144 expression, suggesting the presence of a negative regulatory loop. Furthermore, induced LXR and ABCA1 expression has been related to an estradiol-dependent reduction of lipid accumulation in macrophages and VSMCs [58, 59] suggesting that estrogen tightly regulates lipid content via this miRNA-mediated pathway. Finally, the effect of estrogen on cholesterol efflux is modified by age [178] and this may be related with the dysregulation of miR-144 expression during ageing.

miR-146a is one of the key miRNAs associated with vascular inflammation; it regulates endothelial activation by targeting upstream NF-κB pathway regulators such as TNF receptor associated factor (TRAF) 6 and IL-1 receptor associated kinase (IRAK1) [179] and is described as a marker of senescence-associated proinflammatory status in endothelial cells [180]. In a replicative endothelial cell model, miR-146a downregulation may have caused endothelial senescence by increasing the expression of its direct target, NOX4 [181]. The relationship between miR-146a expression and estrogen has previously reported since circulating miR-146a expression was different between HRT-treated and nontreated postmenopausal genetically identical twins [121]. In addition, estradiol inhibition of miR-146a expression may be a key regulator of lipopolysaccharide-induced interferon-gamma (IFN-γ) expression in lymphocytes [128].

miR-21 expression is also related to estrogens and ageing; increased miR-21 levels have been found in aged heart tissues [182], in senescent vascular cells [164], and in blood samples in elderly people [183]. However, conversely, repression of miR-21 in senescent human aortic endothelial cells seems to increase the expression of antiproliferative and proapoptotic molecules [142] and may represent a diagnostic biomarker for acute myocardial infarction [184]. In cardiac fibroblasts, miR-21 action is implicated in heart hypertrophy by activating MAPK pathways [185], proinflammatory responses in endothelium under oscillatory shear stress [186], and VSMC proliferation after vascular injury [187]. However, the cardiovascular effects of estrogens attenuate these responses; indeed, estradiol downregulates miR-21 by binding to ERs in its promoter region [188] and miR-21 expression in postmenopausal women using HRT was lower than their twin sisters who did not use HRT [121]. Finally, in a murine model of pressure overload-induced cardiac fibrosis, miR-21 was among sex-specific miRNAs regulated by ERβ and was downregulated in estradiol-exposed primary cardiac fibroblasts [135] which may explain sex-dependent differences in cardiac remodeling [189].

miR-34 is part of a well-described family of ageing-associated miRNAs related to cardiomyocyte apoptosis [190] and vascular cell senescence [191, 192]. The expression of miR-34 is elevated in old versus young aorta [173] as well as during ageing and in cardiac pathologies; however, inhibition of the miR-34 family improves heart function [193]. Moreover, miR-34 is influenced by sex and estrogens; miR-34b-3p expression is higher in male rather than female mouse hearts [143]. Furthermore, estradiol exposure decreases miR-34a expression in cultured endothelial cells [194] and is associated with SIRT1-dependent regulation of eNOS. Moreover, blockage of miR-34a expression was more effective in females than in males in a murine model of moderate dilated cardiomyopathy [195], highlighting the importance of studying sex-related differences in miRNA-based therapies.

miR-22 is upregulated in aged hearts [196, 197] and contributes to cardiac hypertrophy by promoting senescence and migratory activity in cardiac fibroblasts [196] and by inhibiting autophagy in cardiomyocytes [197]. Estradiol also appears to decrease miR-22 expression in primary cardiomyocytes via ERα-mediated mechanisms [198]. In addition, miR-22 downregulation increases oxidative defense by increasing expression of its direct target, Sp1 [198]: a regulatory pathway that may explain estradiol-mediated cardioprotection. A reciprocal feedback loop between ERα and miR-22 may be involved in fine-tuning the regulation of estrogen action by posttranscriptionally controlling ERα expression [199].

miR-125 is part of a family of miRNAs which are mainly associated with the activation of inflammatory cells. In macrophages exposed to lipopolysaccharide (LPS), miR-125a is upregulated [200] and miR-125b is downregulated [201]. However, more studies are needed to understand their role in activating or inhibiting inflammatory processes. The regulation of some miR-125 family members is estrogen-dependent: estradiol inhibits NF-κB activity by restoring downregulated miR-125b expression in LPS-stimulated macrophages [201] and both miR-125a and miR-125b are downregulated in lymphocytes exposed to estradiol [128]. Moreover, miR-125 activity is also associated with angiogenesis during ageing: miR-125a-5p expression is increased in endothelial cells from aged mice and is involved in impaired angiogenesis [202].

6. Conclusion

The role of sex hormones in cardiovascular physiology has been extensively studied and has been proposed as the cause of the reported sex-related differences in cardiovascular diseases. Vasodilation, inflammation inhibition, and the action of antioxidants have all been attributed to the effect that estrogens exert on the cardiovascular system. However, the effects that estrogens have on the heart and vascular tissues are themselves modified by ageing. Estrogens modify cardiovascular function by modulating gene expression, and in this sense, miRNAs have emerged as a new regulatory mechanism of both physiological and pathological processes because they regulate gene expression profiles at the posttranscriptional level (Figure 1). Studies on miRNAs have provided insights into cardiovascular function, age-associated physiological changes, and cardiovascular pathologies. However, information about the role of miRNAs in estrogen-dependent processes in cardiovascular ageing is still scarce. Therefore, basic research to analyze sex-specific miRNA regulation can help us to understand differences in cardiovascular diseases between men and women. It may be possible to translate this new knowledge into clinical research, using miRNAs as potential tools for giving diagnoses and/or prognoses, as affordable and noninvasive biomarkers, and as a therapeutic tool for regulating (silencing or increasing) miRNA levels. Thus, future perspectives in miRNA-based therapies should consider the importance of sex-related differences in vascular ageing.

Figure 1

Estrogen-sensitive miRNAs associated with cardiovascular ageing are classified according to their role in the three main mechanisms leading to cardiovascular ageing: cardiovascular remodeling, endothelial dysfunction, and inflammation. (↓) and (↑) indicates increased or decreased expression in cardiovascular tissues during ageing, respectively. Role of estrogens on the expression of represented miRNA is also represented; (−) and (+) indicates negative or positive regulation, respectively. Controversial findings dependent on expression in different tissues/cells are indicated as (↓↑) and (−/+).

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

This work was supported by the Spanish Ministry of Economy and Competitiveness, the Carlos III Health Institute–FEDER-ERDF (grant number PI16/00229), and the COST Action (CA17129: CardioRNA). D. P.-C is funded by a Valencian government/FSE (European Social Fund) fellowship (grant number APOSTD/2018/A/144).

References

C. S. Hayward, R. P. Kelly, and P. Collins, “The roles of gender, the menopause and hormone replacement on cardiovascular function,” Cardiovascular Research, vol. 46, no. 1, pp. 28–49, 2000.
View at: Publisher Site | Google Scholar
M. E. Mendelsohn and R. H. Karas, “The protective effects of estrogen on the cardiovascular system,” The New England Journal of Medicine, vol. 340, no. 23, pp. 1801–1811, 1999.
View at: Publisher Site | Google Scholar
T. S. Mikkola, M. Gissler, M. Merikukka, P. Tuomikoski, and O. Ylikorkala, “Sex differences in age-related cardiovascular mortality,” PLoS One, vol. 8, no. 5, article e63347, 2013.
View at: Publisher Site | Google Scholar
C. Vitale, M. E. Mendelsohn, and G. M. C. Rosano, “Gender differences in the cardiovascular effect of sex hormones,” Nature Reviews. Cardiology, vol. 6, no. 8, pp. 532–542, 2009.
View at: Publisher Site | Google Scholar
V. M. Miller and S. P. Duckles, “Vascular actions of estrogens: functional implications,” Pharmacological Reviews, vol. 60, no. 2, pp. 210–241, 2008.
View at: Publisher Site | Google Scholar
J. A. Simon, J. Hsia, J. A. Cauley et al., “Postmenopausal hormone therapy and risk of stroke: the Heart and Estrogen-Progestin Replacement Study (HERS),” Circulation, vol. 103, no. 5, pp. 638–642, 2001.
View at: Publisher Site | Google Scholar
J. E. Rossouw, R. L. Prentice, J. E. Manson et al., “Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause,” JAMA, vol. 297, no. 13, pp. 1465–1477, 2007.
View at: Publisher Site | Google Scholar
T. B. Clarkson, G. C. Melendez, and S. E. Appt, “Timing hypothesis for postmenopausal hormone therapy: its origin, current status, and future,” Menopause, vol. 20, no. 3, pp. 342–353, 2013.
View at: Publisher Site | Google Scholar
C. López-Otín, M. A. Blasco, L. Partridge, M. Serrano, and G. Kroemer, “The hallmarks of aging,” Cell, vol. 153, no. 6, pp. 1194–1217, 2013.
View at: Publisher Site | Google Scholar
J. M. Ordovás and C. E. Smith, “Epigenetics and cardiovascular disease,” Nature Reviews. Cardiology, vol. 7, no. 9, pp. 510–519, 2010.
View at: Publisher Site | Google Scholar
W. S. Post, P. J. Goldschmidt-Clermont, C. C. Wilhide et al., “Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system,” Cardiovascular Research, vol. 43, no. 4, pp. 985–991, 1999.
View at: Publisher Site | Google Scholar
J. Kim, J. Y. Kim, K. S. Song et al., “Epigenetic changes in estrogen receptor β gene in atherosclerotic cardiovascular tissues and in-vitro vascular senescence,” Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1772, no. 1, pp. 72–80, 2007.
View at: Publisher Site | Google Scholar
D. S. Bendale, P. A. Karpe, R. Chhabra, S. P. Shete, H. Shah, and K. Tikoo, “17-β Oestradiol prevents cardiovascular dysfunction in post-menopausal metabolic syndrome by affecting SIRT1/AMPK/H3 acetylation,” British Journal of Pharmacology, vol. 170, no. 4, pp. 779–795, 2013.
View at: Publisher Site | Google Scholar
D. P. Bartel, “MicroRNAs: genomics, biogenesis, mechanism, and function,” Cell, vol. 116, no. 2, pp. 281–297, 2004.
View at: Publisher Site | Google Scholar
C. Catalanotto, C. Cogoni, and G. Zardo, “MicroRNA in control of gene expression: an overview of nuclear functions,” International Journal of Molecular Sciences, vol. 17, no. 10, p. 1712, 2016.
View at: Publisher Site | Google Scholar
H. Zhu and G.-C. Fan, “Extracellular/circulating microRNAs and their potential role in cardiovascular disease,” American Journal of Cardiovascular Disease, vol. 1, no. 2, pp. 138–149, 2011.
View at: Google Scholar
S. Lee, E. Choi, M.-J. Cha, A.-J. Park, C. Yoon, and K.-C. Hwang, “Impact of miRNAs on cardiovascular aging,” Journal of Geriatric Cardiology, vol. 12, no. 5, pp. 569–574, 2015.
View at: Publisher Site | Google Scholar
C. de Lucia, K. Komici, G. Borghetti et al., “microRNA in cardiovascular aging and age-related cardiovascular diseases,” Frontiers in Medicine, vol. 4, p. 74, 2017.
View at: Publisher Site | Google Scholar
WHO, “Global Health Observatory (GHO) data (World Health Organization),” 2016, http://www.who.int/gho/mortality_burden_disease/causes_death/top_10/en/.
View at: Google Scholar
R. A. Khalil, “Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease,” Biochemical Pharmacology, vol. 86, no. 12, pp. 1627–1642, 2013.
View at: Publisher Site | Google Scholar
C. M. Klinge, “Estrogen receptor interaction with estrogen response elements,” Nucleic Acids Research, vol. 29, no. 14, pp. 2905–2919, 2001.
View at: Publisher Site | Google Scholar
R. O’Lone, K. Knorr, I. Z. Jaffe et al., “Estrogen receptors α and β mediate distinct pathways of vascular gene expression, including genes involved in mitochondrial electron transport and generation of reactive oxygen species,” Molecular Endocrinology, vol. 21, no. 6, pp. 1281–1296, 2007.
View at: Publisher Site | Google Scholar
M. K. Lindberg, S. Moverare, S. Skrtic et al., “Estrogen receptor (ER)-β reduces ERα-regulated gene transcription, supporting a “ying yang” relationship between ERα and ERβ in mice,” Molecular Endocrinology, vol. 17, no. 2, pp. 203–208, 2003.
View at: Publisher Site | Google Scholar
S. Tsutsumi, X. Zhang, K. Takata et al., “Differential regulation of the inducible nitric oxide synthase gene by estrogen receptors 1 and 2,” The Journal of Endocrinology, vol. 199, no. 2, pp. 267–273, 2008.
View at: Publisher Site | Google Scholar
T. Lahm, P. R. Crisostomo, T. A. Markel et al., “Selective estrogen receptor-α and estrogen receptor-β agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide-dependent mechanism,” American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, vol. 295, no. 5, pp. R1486–R1493, 2008.
View at: Publisher Site | Google Scholar
P. A. Arias-Loza, K. Hu, C. Dienesch et al., “Both estrogen receptor subtypes, α and β, attenuate cardiovascular remodeling in aldosterone salt-treated rats,” Hypertension, vol. 50, no. 2, pp. 432–438, 2007.
View at: Publisher Site | Google Scholar
E. Murphy and C. Steenbergen, “Estrogen regulation of protein expression and signaling pathways in the heart,” Biology of Sex Differences, vol. 5, no. 1, p. 6, 2014.
View at: Publisher Site | Google Scholar
G. Pare, Á. Krust, R. H. Karas et al., “Estrogen receptor-α mediates the protective effects of estrogen against vascular injury,” Circulation Research, vol. 90, no. 10, pp. 1087–1092, 2002.
View at: Publisher Site | Google Scholar
J.-F. Arnal, F. Lenfant, R. Metivier et al., “Membrane and nuclear estrogen receptor alpha actions: from tissue specificity to medical implications,” Physiological Reviews, vol. 97, no. 3, pp. 1045–1087, 2017.
View at: Publisher Site | Google Scholar
C. M. Revankar, D. F. Cimino, L. A. Sklar, J. B. Arterburn, and E. R. Prossnitz, “A transmembrane intracellular estrogen receptor mediates rapid cell signaling,” Science, vol. 307, no. 5715, pp. 1625–1630, 2005.
View at: Publisher Site | Google Scholar
T. Kondo, M. Hirose, and K. Kageyama, “Roles of oxidative stress and redox regulation in atherosclerosis,” Journal of Atherosclerosis and Thrombosis, vol. 16, no. 5, pp. 532–538, 2009.
View at: Publisher Site | Google Scholar
M. Barton, “Cholesterol and atherosclerosis: modulation by oestrogen,” Current Opinion in Lipidology, vol. 24, no. 3, pp. 214–220, 2013.
View at: Publisher Site | Google Scholar
V. Miller and S. Mulvagh, “Sex steroids and endothelial function: translating basic science to clinical practice,” Trends in Pharmacological Sciences, vol. 28, no. 6, pp. 263–270, 2007.
View at: Publisher Site | Google Scholar
K. L. Chambliss and P. W. Shaul, “Estrogen modulation of endothelial nitric oxide synthase,” Endocrine Reviews, vol. 23, no. 5, pp. 665–686, 2002.
View at: Publisher Site | Google Scholar
E. Monsalve, P. Oviedo, M. Garciaperez, J. Tarin, A. Cano, and C. Hermenegildo, “Estradiol counteracts oxidized LDL-induced asymmetric dimethylarginine production by cultured human endothelial cells,” Cardiovascular Research, vol. 73, no. 1, pp. 66–72, 2007.
View at: Publisher Site | Google Scholar
S. Novella, A. Laguna-Fernández, M. Lázaro-Franco et al., “Estradiol, acting through estrogen receptor alpha, restores dimethylarginine dimethylaminohydrolase activity and nitric oxide production in oxLDL-treated human arterial endothelial cells,” Molecular and Cellular Endocrinology, vol. 365, no. 1, pp. 11–16, 2013.
View at: Publisher Site | Google Scholar
A. Sobrino, P. J. Oviedo, S. Novella et al., “Estradiol selectively stimulates endothelial prostacyclin production through estrogen receptor-α,” Journal of Molecular Endocrinology, vol. 44, no. 4, pp. 237–246, 2010.
View at: Publisher Site | Google Scholar
R. K. Dubey, E. K. Jackson, P. J. Keller, B. Imthurn, and M. Rosselli, “Estradiol metabolites inhibit endothelin synthesis by an estrogen receptor-independent mechanism,” Hypertension, vol. 37, no. 2, pp. 640–644, 2001.
View at: Publisher Site | Google Scholar
S. H. Juan, J. J. Chen, C. H. Chen et al., “17β-estradiol inhibits cyclic strain-induced endothelin-1 gene expression within vascular endothelial cells,” American Journal of Physiology. Heart and Circulatory Physiology, vol. 287, no. 3, pp. H1254–H1261, 2004.
View at: Publisher Site | Google Scholar
A. Suzuki, K. Mizuno, Y. Ino et al., “Effects of 17β-estradiol and progesterone on growth-factor-induced proliferation and migration in human female aortic smooth muscle cells in vitro,” Cardiovascular Research, vol. 32, no. 3, pp. 516–523, 1996.
View at: Google Scholar
A. Mügge, M. Riedel, M. Barton, M. Kuhn, and P. R. Lichtlen, “Endothelium independent relaxation of human coronary arteries by 17β-oestradiol in vitro,” Cardiovascular Research, vol. 27, no. 11, pp. 1939–1942, 1993.
View at: Publisher Site | Google Scholar
J. K. Crews and R. A. Khalil, “Antagonistic effects of 17β-estradiol, progesterone, and testosterone on Ca²⁺ entry mechanisms of coronary vasoconstriction,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 19, no. 4, pp. 1034–1040, 1999.
View at: Publisher Site | Google Scholar
R. E. White, G. Han, M. Maunz et al., “Endothelium-independent effect of estrogen on Ca²⁺−activated K⁺ channels in human coronary artery smooth muscle cells,” Cardiovascular Research, vol. 53, no. 3, pp. 650–661, 2002.
View at: Publisher Site | Google Scholar
J. Hiroki, H. Shimokawa, Y. Mukai, T. Ichiki, and A. Takeshita, “Divergent effects of estrogen and nicotine on Rho-kinase expression in human coronary vascular smooth muscle cells,” Biochemical and Biophysical Research Communications, vol. 326, no. 1, pp. 154–159, 2004.
View at: Publisher Site | Google Scholar
C. A. Kanashiro and R. A. Khalil, “Gender-related distinctions in protein kinase C activity in rat vascular smooth muscle,” American Journal of Physiology. Cell Physiology, vol. 280, no. 1, pp. C34–C45, 2001.
View at: Publisher Site | Google Scholar
K. Komukai, S. Mochizuki, and M. Yoshimura, “Gender and the renin–angiotensin–aldosterone system,” Fundamental & Clinical Pharmacology, vol. 24, no. 6, pp. 687–698, 2010.
View at: Publisher Site | Google Scholar
A. Mompeón, M. Lázaro-Franco, C. Bueno-Betí et al., “Estradiol, acting through ERα, induces endothelial non-classic renin-angiotensin system increasing angiotensin 1–7 production,” Molecular and Cellular Endocrinology, vol. 422, pp. 1–8, 2016.
View at: Publisher Site | Google Scholar
G. Nickenig, A. T. Bäumer, C. Grohè et al., “Estrogen modulates AT₁ receptor gene expression in vitro and in vivo,” Circulation, vol. 97, no. 22, pp. 2197–2201, 1998.
View at: Publisher Site | Google Scholar
A. Sobrino, S. Vallejo, S. Novella et al., “Mas receptor is involved in the estrogen-receptor induced nitric oxide-dependent vasorelaxation,” Biochemical Pharmacology, vol. 129, pp. 67–72, 2017.
View at: Publisher Site | Google Scholar
R. H. Straub, “The complex role of estrogens in inflammation,” Endocrine Reviews, vol. 28, no. 5, pp. 521–574, 2007.
View at: Publisher Site | Google Scholar
Á. Álvarez, C. Hermenegildo, A. C. Issekutz, J. V. Esplugues, and M. J. Sanz, “Estrogens inhibit angiotensin II-induced leukocyte-endothelial cell interactions in vivo via rapid endothelial nitric oxide synthase and cyclooxygenase activation,” Circulation Research, vol. 91, no. 12, pp. 1142–1150, 2002.
View at: Publisher Site | Google Scholar
M. Abu-Taha, C. Rius, C. Hermenegildo et al., “Menopause and ovariectomy cause a low grade of systemic inflammation that may be prevented by chronic treatment with low doses of estrogen or losartan,” Journal of Immunology, vol. 183, no. 2, pp. 1393–1402, 2009.
View at: Publisher Site | Google Scholar
A. P. Miller, W. Feng, D. Xing et al., “Estrogen modulates inflammatory mediator expression and neutrophil chemotaxis in injured arteries,” Circulation, vol. 110, no. 12, pp. 1664–1669, 2004.
View at: Publisher Site | Google Scholar
D. Xing, A. Miller, L. Novak, R. Rocha, Y. F. Chen, and S. Oparil, “Estradiol and progestins differentially modulate leukocyte infiltration after vascular injury,” Circulation, vol. 109, no. 2, pp. 234–241, 2004.
View at: Publisher Site | Google Scholar
A. H. Wagner, M. R. Schroeter, and M. Hecker, “17β-estradiol inhibition of NADPH oxidase expression in human endothelial cells,” The FASEB Journal, vol. 15, no. 12, pp. 2121–2130, 2001.
View at: Publisher Site | Google Scholar
K. Strehlow, S. Rotter, S. Wassmann et al., “Modulation of antioxidant enzyme expression and function by estrogen,” Circulation Research, vol. 93, no. 2, pp. 170–177, 2003.
View at: Publisher Site | Google Scholar
Z. Liu, Y. Gou, H. Zhang et al., “Estradiol improves cardiovascular function through up-regulation of SOD2 on vascular wall,” Redox Biology, vol. 3, pp. 88–99, 2014.
View at: Publisher Site | Google Scholar
J. A. McCrohon, S. Nakhla, W. Jessup, K. K. Stanley, and D. S. Celermajer, “Estrogen and progesterone reduce lipid accumulation in human monocyte-derived macrophages: a sex-specific effect,” Circulation, vol. 100, no. 23, pp. 2319–2325, 1999.
View at: Publisher Site | Google Scholar
H. Wang, Y. Liu, L. Zhu et al., “17β-estradiol promotes cholesterol efflux from vascular smooth muscle cells through a liver X receptor α-dependent pathway,” International Journal of Molecular Medicine, vol. 33, no. 3, pp. 550–558, 2014.
View at: Publisher Site | Google Scholar
B. A. Walsh, A. E. Mullick, R. L. Walzem, and J. C. Rutledge, “17β-estradiol reduces tumor necrosis factor-α-mediated LDL accumulation in the artery wall,” Journal of Lipid Research, vol. 40, no. 3, pp. 387–396, 1999.
View at: Google Scholar
N. Townsend, L. Wilson, P. Bhatnagar, K. Wickramasinghe, M. Rayner, and M. Nichols, “Cardiovascular disease in Europe: epidemiological update 2016,” European Heart Journal, vol. 37, no. 42, pp. 3232–3245, 2016.
View at: Publisher Site | Google Scholar
A. A. Merz and S. Cheng, “Sex differences in cardiovascular ageing,” Heart, vol. 102, no. 11, pp. 825–831, 2016.
View at: Publisher Site | Google Scholar
R. A. Lobo, “Hormone-replacement therapy: current thinking,” Nature Reviews. Endocrinology, vol. 13, no. 4, pp. 220–231, 2017.
View at: Publisher Site | Google Scholar
J. D. Erusalimsky, “Vascular endothelial senescence: from mechanisms to pathophysiology,” Journal of Applied Physiology, vol. 106, no. 1, pp. 326–332, 2009.
View at: Publisher Site | Google Scholar
J. O. Fajemiroye, L. C. Cunha, R. Saavedra-Rodríguez et al., “Aging-induced biological changes and cardiovascular diseases,” BioMed Research International, vol. 2018, Article ID 7156435, 14 pages, 2018.
View at: Publisher Site | Google Scholar
K. L. Moreau and K. L. Hildreth, “Vascular aging across the menopause transition in healthy women,” Advances in Vascular Medicine, vol. 2014, Article ID 204390, 12 pages, 2014.
View at: Publisher Site | Google Scholar
C. J. Nicholson, M. Sweeney, S. C. Robson, and M. J. Taggart, “Estrogenic vascular effects are diminished by chronological aging,” Scientific Reports, vol. 7, no. 1, article 12153, 2017.
View at: Publisher Site | Google Scholar
M. D. Herrera, C. Mingorance, R. Rodríguez-Rodríguez, and M. Alvarez de Sotomayor, “Endothelial dysfunction and aging: an update,” Ageing Research Reviews, vol. 9, no. 2, pp. 142–152, 2010.
View at: Publisher Site | Google Scholar
L. Rodríguez-Mañas, M. el-Assar, S. Vallejo et al., “Endothelial dysfunction in aged humans is related with oxidative stress and vascular inflammation,” Aging Cell, vol. 8, no. 3, pp. 226–238, 2009.
View at: Publisher Site | Google Scholar
S. Novella, A. P. Dantas, G. Segarra et al., “Gathering of aging and estrogen withdrawal in vascular dysfunction of senescent accelerated mice,” Experimental Gerontology, vol. 45, no. 11, pp. 868–874, 2010.
View at: Publisher Site | Google Scholar
S. Novella, A. P. Dantas, G. Segarra et al., “Aging-related endothelial dysfunction in the aorta from female senescence-accelerated mice is associated with decreased nitric oxide synthase expression,” Experimental Gerontology, vol. 48, no. 11, pp. 1329–1337, 2013.
View at: Publisher Site | Google Scholar
S. B. A. Cau, F. S. Carneiro, and R. C. Tostes, “Differential modulation of nitric oxide synthases in aging: therapeutic opportunities,” Frontiers in Physiology, vol. 3, p. 218, 2012.
View at: Publisher Site | Google Scholar
Y.-I. Yoshida, S. Eda, and M. Masada, “Alterations of tetrahydrobiopterin biosynthesis and pteridine levels in mouse tissues during growth and aging,” Brain and Development, vol. 22, pp. 45–49, 2000.
View at: Publisher Site | Google Scholar
Y. Xiong, L. W. Yuan, H. W. Deng, Y. J. Li, and B. M. Chen, “Elevated serum endogenous inhibitor of nitric oxide synthase and endothelial dysfunction in aged rats,” Clinical and Experimental Pharmacology & Physiology, vol. 28, no. 10, pp. 842–847, 2001.
View at: Publisher Site | Google Scholar
S. Novella, A. P. Dantas, G. Segarra et al., “Aging enhances contraction to thromboxane A₂ in aorta from female senescence-accelerated mice,” Age, vol. 35, no. 1, pp. 117–128, 2013.
View at: Publisher Site | Google Scholar
V. B. O’Donnell and B. A. Freeman, “Interactions between nitric oxide and lipid oxidation pathways,” Circulation Research, vol. 88, no. 1, pp. 12–21, 2001.
View at: Publisher Site | Google Scholar
M. El Assar, J. Angulo, and L. Rodríguez-Mañas, “Oxidative stress and vascular inflammation in aging,” Free Radical Biology & Medicine, vol. 65, pp. 380–401, 2013.
View at: Publisher Site | Google Scholar
L. S. Kang, B. Chen, R. A. Reyes et al., “Aging and estrogen alter endothelial reactivity to reactive oxygen species in coronary arterioles,” American Journal of Physiology. Heart and Circulatory Physiology, vol. 300, no. 6, pp. H2105–H2115, 2011.
View at: Publisher Site | Google Scholar
X. Vidal-Gomez, S. Novella, I. Perez-Monzo et al., “Decreased bioavailability of nitric oxide in aorta from ovariectomized senescent mice. Role of cyclooxygenase,” Experimental Gerontology, vol. 76, pp. 1–8, 2016.
View at: Publisher Site | Google Scholar
B. A. Monk and S. J. George, “The effect of ageing on vascular smooth muscle cell behaviour - a mini-review,” Gerontology, vol. 61, no. 5, pp. 416–426, 2015.
View at: Publisher Site | Google Scholar
B. P. McGrath, Y.-L. Liang, H. Teede, L. M. Shiel, J. D. Cameron, and A. Dart, “Age-related deterioration in arterial structure and function in postmenopausal women,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 18, no. 7, pp. 1149–1156, 1998.
View at: Publisher Site | Google Scholar
Y. Zhang, K. G. Stewart, and S. T. Davidge, “Estrogen replacement reduces age-associated remodeling in rat mesenteric arteries,” Hypertension, vol. 36, no. 6, pp. 970–974, 2000.
View at: Publisher Site | Google Scholar
K. C. Lewandowski, J. Komorowski, D. P. Mikhalidis et al., “Effects of hormone replacement therapy type and route of administration on plasma matrix metalloproteinases and their tissue inhibitors in postmenopausal women,” The Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 8, pp. 3123–3130, 2006.
View at: Publisher Site | Google Scholar
P. Lacolley, V. Regnault, and A. P. Avolio, “Smooth muscle cell and arterial aging: basic and clinical aspects,” Cardiovascular Research, vol. 114, no. 4, pp. 513–528, 2018.
View at: Publisher Site | Google Scholar
H. Qiu, B. Tian, R. G. Resuello et al., “Sex-specific regulation of gene expression in the aging monkey aorta,” Physiological Genomics, vol. 29, no. 2, pp. 169–180, 2007.
View at: Publisher Site | Google Scholar
T. Mori, J. Durand, Y.-F. Chen, J. A. Thompson, S. Bakir, and S. Oparil, “Effects of short-term estrogen treatment on the neointimal response to balloon injury of rat carotid artery,” The American Journal of Cardiology, vol. 85, no. 10, pp. 1276–1279, 2000.
View at: Publisher Site | Google Scholar
C. Franceschi, P. Garagnani, G. Vitale, M. Capri, and S. Salvioli, “Inflammaging and ‘Garb-aging’,” Trends in Endocrinology & Metabolism, vol. 28, no. 3, pp. 199–212, 2017.
View at: Publisher Site | Google Scholar
A. Csiszar, M. Wang, E. G. Lakatta, and Z. Ungvari, “Inflammation and endothelial dysfunction during aging: role of NF-κB,” Journal of Applied Physiology, vol. 105, no. 4, pp. 1333–1341, 2008.
View at: Publisher Site | Google Scholar
S. Novella, M. Heras, C. Hermenegildo, and A. P. Dantas, “Effects of estrogen on vascular inflammation: a matter of timing,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, no. 8, pp. 2035–2042, 2012.
View at: Publisher Site | Google Scholar
M. R. Bowling, D. Xing, A. Kapadia et al., “Estrogen effects on vascular inflammation are age dependent: role of estrogen receptors,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 34, no. 7, pp. 1477–1485, 2014.
View at: Publisher Site | Google Scholar
L. Novensà, S. Novella, P. Medina et al., “Aging negatively affects estrogens-mediated effects on nitric oxide bioavailability by shifting ERα/ERβ balance in female mice,” PLoS One, vol. 6, no. 9, article e25335, 2011.
View at: Publisher Site | Google Scholar
Y. S. Rao, N. N. Mott, Y. Wang, W. C. J. Chung, and T. R. Pak, “MicroRNAs in the aging female brain: a putative mechanism for age-specific estrogen effects,” Endocrinology, vol. 154, no. 8, pp. 2795–2806, 2013.
View at: Publisher Site | Google Scholar
D. Guo, Y. Ye, J. Qi et al., “Age and sex differences in microRNAs expression during the process of thymus aging,” Acta Biochimica et Biophysica Sinica, vol. 49, no. 5, pp. 409–419, 2017.
View at: Publisher Site | Google Scholar
J. C. Kwekel, V. Vijay, V. G. Desai, C. L. Moland, and J. C. Fuscoe, “Age and sex differences in kidney microRNA expression during the life span of F344 rats,” Biology of Sex Differences, vol. 6, no. 1, p. 1, 2015.
View at: Publisher Site | Google Scholar
G. Cizeron-Clairac, F. Lallemand, S. Vacher, R. Lidereau, I. Bieche, and C. Callens, “MiR-190b, the highest up-regulated miRNA in ERα-positive compared to ERα-negative breast tumors, a new biomarker in breast cancers?” BMC Cancer, vol. 15, no. 1, p. 499, 2015.
View at: Publisher Site | Google Scholar
S. T. Bailey, T. Westerling, and M. Brown, “Loss of estrogen-regulated microRNA expression increases HER2 signaling and is prognostic of poor outcome in luminal breast cancer,” Cancer Research, vol. 75, no. 2, pp. 436–445, 2015.
View at: Publisher Site | Google Scholar
J. Zhao, G. A. Imbrie, W. E. Baur et al., “Estrogen receptor-mediated regulation of microRNA inhibits proliferation of vascular smooth muscle cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 33, no. 2, pp. 257–265, 2013.
View at: Publisher Site | Google Scholar
X. Vidal-Gómez, D. Pérez-Cremades, A. Mompeón, A. P. Dantas, S. Novella, and C. Hermenegildo, “microRNA as crucial regulators of gene expression in estradiol-treated human endothelial cells,” Cellular Physiology and Biochemistry, vol. 45, no. 5, pp. 1878–1892, 2018.
View at: Publisher Site | Google Scholar
R. Song, S. Ro, J. D. Michaels, C. Park, J. R. McCarrey, and W. Yan, “Many X-linked microRNAs escape meiotic sex chromosome inactivation,” Nature Genetics, vol. 41, no. 4, pp. 488–493, 2009.
View at: Publisher Site | Google Scholar
B. R. Migeon, “The role of x inactivation and cellular mosaicism in women’s health and sex-specific diseases,” JAMA, vol. 295, no. 12, pp. 1428–1433, 2006.
View at: Publisher Site | Google Scholar
B. W. Florijn, R. Bijkerk, E. P. van der Veer, and A. J. van Zonneveld, “Gender and cardiovascular disease: are sex-biased microRNA networks a driving force behind heart failure with preserved ejection fraction in women?” Cardiovascular Research, vol. 114, no. 2, pp. 210–225, 2018.
View at: Publisher Site | Google Scholar
V. N. Kim, J. Han, and M. C. Siomi, “Biogenesis of small RNAs in animals,” Nature Reviews. Molecular Cell Biology, vol. 10, no. 2, pp. 126–139, 2009.
View at: Publisher Site | Google Scholar
C. Borrás, E. Serna, J. Gambini, M. Inglés, and J. Vina, “Centenarians maintain miRNA biogenesis pathway while it is impaired in octogenarians,” Mechanisms of Ageing and Development, vol. 168, pp. 54–57, 2017.
View at: Publisher Site | Google Scholar
Z. Ungvari, Z. Tucsek, D. Sosnowska et al., “Aging-induced dysregulation of Dicer1-dependent microRNA expression impairs angiogenic capacity of rat cerebromicrovascular endothelial cells,” The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, vol. 68, no. 8, pp. 877–891, 2013.
View at: Publisher Site | Google Scholar
W. J. Yang, D. D. Yang, S. Na, G. E. Sandusky, Q. Zhang, and G. Zhao, “Dicer is required for embryonic angiogenesis during mouse development,” The Journal of Biological Chemistry, vol. 280, no. 10, pp. 9330–9335, 2005.
View at: Publisher Site | Google Scholar
Y. Suarez, C. Fernandez-Hernando, J. S. Pober, and W. C. Sessa, “Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells,” Circulation Research, vol. 100, no. 8, pp. 1164–1173, 2007.
View at: Publisher Site | Google Scholar
A. Kuehbacher, C. Urbich, A. M. Zeiher, and S. Dimmeler, “Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis,” Circulation Research, vol. 101, no. 1, pp. 59–68, 2007.
View at: Publisher Site | Google Scholar
A. Gupta, E. Caffrey, G. Callagy, and S. Gupta, “Oestrogen-dependent regulation of miRNA biogenesis: many ways to skin the cat,” Biochemical Society Transactions, vol. 40, no. 4, pp. 752–758, 2012.
View at: Publisher Site | Google Scholar
C. Cheng, X. Fu, P. Alves, and M. Gerstein, “mRNA expression profiles show differential regulatory effects of microRNAs between estrogen receptor-positive and estrogen receptor-negative breast cancer,” Genome Biology, vol. 10, no. 9, p. R90, 2009.
View at: Publisher Site | Google Scholar
P. Bhat-Nakshatri, G. Wang, N. R. Collins et al., “Estradiol-regulated microRNAs control estradiol response in breast cancer cells,” Nucleic Acids Research, vol. 37, no. 14, pp. 4850–4861, 2009.
View at: Publisher Site | Google Scholar
O. Paris, L. Ferraro, O. M. V. Grober et al., “Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer,” Oncogene, vol. 31, no. 38, pp. 4196–4206, 2012.
View at: Publisher Site | Google Scholar
W. B. Nothnick, C. Healy, and X. Hong, “Steroidal regulation of uterine miRNAs is associated with modulation of the miRNA biogenesis components Exportin-5 and Dicer1,” Endocrine, vol. 37, no. 2, pp. 265–273, 2010.
View at: Publisher Site | Google Scholar
D. Pérez-Cremades, A. Mompeón, X. Vidal-Gómez, C. Hermenegildo, and S. Novella, “miRNA as a new regulatory mechanism of estrogen vascular action,” International Journal of Biological Sciences, vol. 19, no. 2, p. 473, 2018.
View at: Publisher Site | Google Scholar
J. H. An, J. H. Ohn, J. A. Song et al., “Changes of microRNA profile and microRNA-mRNA regulatory network in bones of ovariectomized mice,” Journal of Bone and Mineral Research, vol. 29, no. 3, pp. 644–656, 2014.
View at: Publisher Site | Google Scholar
J. Chen, K. Li, Q. Pang et al., “Identification of suitable reference gene and biomarkers of serum miRNAs for osteoporosis,” Scientific Reports, vol. 6, no. 1, article 36347, 2016.
View at: Publisher Site | Google Scholar
F. Olivieri, M. Ahtiainen, R. Lazzarini et al., “Hormone replacement therapy enhances IGF-1 signaling in skeletal muscle by diminishing miR-182 and miR-223 expressions: a study on postmenopausal monozygotic twin pairs,” Aging Cell, vol. 13, no. 5, pp. 850–861, 2014.
View at: Publisher Site | Google Scholar
R. Kangas, C. Morsiani, G. Pizza et al., “Menopause and adipose tissue: miR-19a-3p is sensitive to hormonal replacement,” Oncotarget, vol. 9, no. 2, pp. 2279–2294, 2018.
View at: Publisher Site | Google Scholar
P. Vrtacnik, B. Ostanek, S. Mencej-Bedrac, and J. Marc, “The many faces of estrogen signaling,” Biochemical Medicine, vol. 24, no. 3, pp. 329–342, 2014.
View at: Publisher Site | Google Scholar
Y.-M. Park, C. Erickson, D. Bessesen, R. E. Van Pelt, and K. Cox-York, “Age- and menopause-related differences in subcutaneous adipose tissue estrogen receptor mRNA expression,” Steroids, vol. 121, pp. 17–21, 2017.
View at: Publisher Site | Google Scholar
H. Yamatani, K. Takahashi, T. Yoshida, T. Soga, and H. Kurachi, “Differences in the fatty acid metabolism of visceral adipose tissue in postmenopausal women,” Menopause, vol. 21, no. 2, pp. 170–176, 2014.
View at: Publisher Site | Google Scholar
R. Kangas, E. Pollanen, M. R. Rippo et al., “Circulating miR-21, miR-146a and Fas ligand respond to postmenopausal estrogen-based hormone replacement therapy--a study with monozygotic twin pairs,” Mechanisms of Ageing and Development, vol. 143-144, pp. 1–8, 2014.
View at: Publisher Site | Google Scholar
R. Kangas, T. Tormakangas, V. Fey et al., “Aging and serum exomiR content in women-effects of estrogenic hormone replacement therapy,” Scientific Reports, vol. 7, no. 1, article 42702, 2017.
View at: Publisher Site | Google Scholar
J. E. Fish, M. M. Santoro, S. U. Morton et al., “miR-126 regulates angiogenic signaling and vascular integrity,” Developmental Cell, vol. 15, no. 2, pp. 272–284, 2008.
View at: Publisher Site | Google Scholar
S. Wang, A. B. Aurora, B. A. Johnson et al., “The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis,” Developmental Cell, vol. 15, no. 2, pp. 261–271, 2008.
View at: Publisher Site | Google Scholar
T. A. Harris, M. Yamakuchi, M. Ferlito, J. T. Mendell, and C. J. Lowenstein, “MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 5, pp. 1516–1521, 2008.
View at: Publisher Site | Google Scholar
J. Zhou, Y. S. Li, P. Nguyen et al., “Regulation of vascular smooth muscle cell turnover by endothelial cell-secreted microRNA-126: role of shear stress,” Circulation Research, vol. 113, no. 1, pp. 40–51, 2013.
View at: Publisher Site | Google Scholar
P. Li, J. Wei, X. Li et al., “17β-estradiol enhances vascular endothelial Ets-1/miR-126-3p expression: the possible mechanism for attenuation of atherosclerosis,” The Journal of Clinical Endocrinology and Metabolism, vol. 102, no. 2, pp. 594–603, 2017.
View at: Publisher Site | Google Scholar
R. Dai, R. A. Phillips, Y. Zhang, D. Khan, O. Crasta, and S. A. Ahmed, “Suppression of LPS-induced interferon-γ and nitric oxide in splenic lymphocytes by select estrogen-regulated microRNAs: a novel mechanism of immune modulation,” Blood, vol. 112, no. 12, pp. 4591–4597, 2008.
View at: Publisher Site | Google Scholar
F. Jansen, T. Stumpf, S. Proebsting et al., “Intercellular transfer of miR-126-3p by endothelial microparticles reduces vascular smooth muscle cell proliferation and limits neointima formation by inhibiting LRP6,” Journal of Molecular and Cellular Cardiology, vol. 104, pp. 43–52, 2017.
View at: Publisher Site | Google Scholar
D. A. Chistiakov, A. N. Orekhov, and Y. V. Bobryshev, “The role of miR-126 in embryonic angiogenesis, adult vascular homeostasis, and vascular repair and its alterations in atherosclerotic disease,” Journal of Molecular and Cellular Cardiology, vol. 97, pp. 47–55, 2016.
View at: Publisher Site | Google Scholar
Y. Fukushima, M. Nakanishi, H. Nonogi, Y. Goto, and N. Iwai, “Assessment of plasma miRNAs in congestive heart failure,” Circulation Journal, vol. 75, no. 2, pp. 336–340, 2011.
View at: Publisher Site | Google Scholar
H. Li, X. Zhao, Y. Z. Liu et al., “Plasma microRNA-126-5p is associated with the complexity and severity of coronary artery disease in patients with stable angina pectoris,” Cellular Physiology and Biochemistry, vol. 39, no. 3, pp. 837–846, 2016.
View at: Publisher Site | Google Scholar
A. ElSharawy, A. Keller, F. Flachsbart et al., “Genome-wide miRNA signatures of human longevity,” Aging Cell, vol. 11, no. 4, pp. 607–616, 2012.
View at: Publisher Site | Google Scholar
F. Olivieri, M. Bonafè, L. Spazzafumo et al., “Age- and glycemia-related miR-126-3p levels in plasma and endothelial cells,” Aging, vol. 6, no. 9, pp. 771–786, 2014.
View at: Publisher Site | Google Scholar
A. M. Queirós, C. Eschen, D. Fliegner et al., “Sex- and estrogen-dependent regulation of a miRNA network in the healthy and hypertrophied heart,” International Journal of Cardiology, vol. 169, no. 5, pp. 331–338, 2013.
View at: Publisher Site | Google Scholar
M. Hackl, S. Brunner, K. Fortschegger et al., “miR-17, miR-19b, miR-20a, and miR-106a are down-regulated in human aging,” Aging Cell, vol. 9, no. 2, pp. 291–296, 2010.
View at: Publisher Site | Google Scholar
H. Zhang, H. Yang, C. Zhang et al., “Investigation of microRNA expression in human serum during the aging process,” The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, vol. 70, no. 1, pp. 102–109, 2015.
View at: Publisher Site | Google Scholar
J. Zhang, S.-F. Li, H. Chen, and J.-X. Song, “MiR-106b-5p inhibits tumor necrosis factor-α-induced apoptosis by targeting phosphatase and tensin homolog deleted on chromosome 10 in vascular endothelial cells,” Chinese Medical Journal, vol. 129, no. 12, pp. 1406–1412, 2016.
View at: Publisher Site | Google Scholar
Z. Liu, D. Yang, P. Xie et al., “MiR-106b and MiR-15b modulate apoptosis and angiogenesis in myocardial infarction,” Cellular Physiology and Biochemistry, vol. 29, no. 5-6, pp. 851–862, 2012.
View at: Publisher Site | Google Scholar
E. M. Noh, Y. R. Lee, K. O. Chay et al., “Estrogen receptor α induces down-regulation of PTEN through PI3-kinase activation in breast cancer cells,” Molecular Medicine Reports, vol. 4, no. 2, pp. 215–219, 2011.
View at: Publisher Site | Google Scholar
J. A. Smith, R. Zhang, A. K. Varma, A. Das, S. K. Ray, and N. L. Banik, “Estrogen partially down-regulates PTEN to prevent apoptosis in VSC4.1 motoneurons following exposure to IFN-γ,” Brain Research, vol. 1301, pp. 163–170, 2009.
View at: Publisher Site | Google Scholar
C. Rippe, M. Blimline, K. A. Magerko et al., “MicroRNA changes in human arterial endothelial cells with senescence: relation to apoptosis, eNOS and inflammation,” Experimental Gerontology, vol. 47, no. 1, pp. 45–51, 2012.
View at: Publisher Site | Google Scholar
A. M. Evangelista, A. M. Deschamps, D. Liu, N. Raghavachari, and E. Murphy, “miR-222 contributes to sex-dimorphic cardiac eNOS expression via ets-1,” Physiological Genomics, vol. 45, no. 12, pp. 493–498, 2013.
View at: Publisher Site | Google Scholar
B. Ostadal and P. Ostadal, “Sex-based differences in cardiac ischaemic injury and protection: therapeutic implications,” British Journal of Pharmacology, vol. 171, no. 3, pp. 541–554, 2014.
View at: Publisher Site | Google Scholar
G. Di Leva, P. Gasparini, C. Piovan et al., “MicroRNA cluster 221-222 and estrogen receptor α interactions in breast cancer,” Journal of the National Cancer Institute, vol. 102, no. 10, pp. 706–721, 2010.
View at: Publisher Site | Google Scholar
X. Liu, Y. Cheng, S. Zhang, Y. Lin, J. Yang, and C. Zhang, “A necessary role of miR-221 and miR-222 in vascular smooth muscle cell proliferation and neointimal hyperplasia,” Circulation Research, vol. 104, no. 4, pp. 476–487, 2009.
View at: Publisher Site | Google Scholar
K. R. Cordes, N. T. Sheehy, M. P. White et al., “miR-145 and miR-143 regulate smooth muscle cell fate decisions,” Nature, vol. 460, pp. 705–710, 2009.
View at: Publisher Site | Google Scholar
T. Boettger, N. Beetz, S. Kostin et al., “Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster,” The Journal of Clinical Investigation, vol. 119, no. 9, pp. 2634–2647, 2009.
View at: Publisher Site | Google Scholar
E. Hergenreider, S. Heydt, K. Tréguer et al., “Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs,” Nature Cell Biology, vol. 14, no. 3, pp. 249–256, 2012.
View at: Publisher Site | Google Scholar
L. Deng, F. J. Blanco, H. Stevens et al., “MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension,” Circulation Research, vol. 117, no. 10, pp. 870–883, 2015.
View at: Publisher Site | Google Scholar
J. Faccini, J.-B. Ruidavets, P. Cordelier et al., “Circulating miR-155, miR-145 and let-7c as diagnostic biomarkers of the coronary artery disease,” Scientific Reports, vol. 7, no. 1, article 42916, 2017.
View at: Publisher Site | Google Scholar
S. Kuokkanen, B. Chen, L. Ojalvo, L. Benard, N. Santoro, and J. W. Pollard, “Genomic profiling of microRNAs and messenger RNAs reveals hormonal regulation in microRNA expression in human endometrium,” Biology of Reproduction, vol. 82, no. 4, pp. 791–801, 2010.
View at: Publisher Site | Google Scholar
N. Mellios, M. Galdzicka, E. Ginns et al., “Gender-specific reduction of estrogen-sensitive small RNA, miR-30b, in subjects with schizophrenia,” Schizophrenia Bulletin, vol. 38, no. 3, pp. 433–443, 2012.
View at: Publisher Site | Google Scholar
Y. F. Liu, A. Spinelli, L. Y. Sun et al., “MicroRNA-30 inhibits neointimal hyperplasia by targeting Ca ²⁺/calmodulin-dependent protein kinase IIδ (CaMKIIδ),” Scientific Reports, vol. 6, no. 1, article 26166, 2016.
View at: Publisher Site | Google Scholar
Y. Huang, J. Chen, Y. Zhou et al., “Circulating miR-30 is related to carotid artery atherosclerosis,” Clinical and Experimental Hypertension, vol. 38, no. 5, pp. 489–494, 2016.
View at: Publisher Site | Google Scholar
C. Jentzsch, S. Leierseder, X. Loyer et al., “A phenotypic screen to identify hypertrophy-modulating microRNAs in primary cardiomyocytes,” Journal of Molecular and Cellular Cardiology, vol. 52, no. 1, pp. 13–20, 2012.
View at: Publisher Site | Google Scholar
W. Pan, Y. Zhong, C. Cheng et al., “MiR-30-regulated autophagy mediates angiotensin II-induced myocardial hypertrophy,” PLoS One, vol. 8, no. 1, article e53950, 2013.
View at: Publisher Site | Google Scholar
Y. Shen, Z. Shen, L. Miao et al., “miRNA-30 family inhibition protects against cardiac ischemic injury by regulating cystathionine-γ-lyase expression,” Antioxidants & Redox Signaling, vol. 22, no. 3, pp. 224–240, 2015.
View at: Publisher Site | Google Scholar
G. Bridge, R. Monteiro, S. Henderson et al., “The microRNA-30 family targets DLL4 to modulate endothelial cell behavior during angiogenesis,” Blood, vol. 120, no. 25, pp. 5063–5072, 2012.
View at: Publisher Site | Google Scholar
S. Demolli, C. Doebele, A. Doddaballapur et al., “MicroRNA-30 mediates anti-inflammatory effects of shear stress and KLF2 via repression of angiopoietin 2,” Journal of Molecular and Cellular Cardiology, vol. 88, pp. 111–119, 2015.
View at: Publisher Site | Google Scholar
F. Li, Q. Chen, X. Song, L. Zhou, and J. Zhang, “MiR-30b is involved in the homocysteine-induced apoptosis in human coronary artery endothelial cells by regulating the expression of caspase 3,” International Journal of Molecular Sciences, vol. 16, no. 8, pp. 17682–17695, 2015.
View at: Publisher Site | Google Scholar
D. Xing, S. Nozell, Y.-F. Chen, F. Hage, and S. Oparil, “Estrogen and mechanisms of vascular protection,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, no. 3, pp. 289–295, 2009.
View at: Publisher Site | Google Scholar
C. Bang, J. A. N. Fiedler, and T. Thum, “Cardiovascular importance of the microRNA-23/27/24 family,” Microcirculation, vol. 19, no. 3, pp. 208–214, 2012.
View at: Publisher Site | Google Scholar
H. Dellago, B. Preschitz-Kammerhofer, L. Terlecki-Zaniewicz et al., “High levels of oncomiR-21 contribute to the senescence-induced growth arrest in normal human cells and its knock-down increases the replicative lifespan,” Aging Cell, vol. 12, no. 3, pp. 446–458, 2013.
View at: Publisher Site | Google Scholar
Z. Luo, X. Feng, H. Wang et al., “Mir-23a induces telomere dysfunction and cellular senescence by inhibiting TRF2 expression,” Aging Cell, vol. 14, no. 3, pp. 391–399, 2015.
View at: Publisher Site | Google Scholar
N. Wang, L.-Y. Sun, S.-C. Zhang et al., “MicroRNA-23a participates in estrogen deficiency induced gap junction remodeling of rats by targeting GJA1,” International Journal of Biological Sciences, vol. 11, no. 4, pp. 390–403, 2015.
View at: Publisher Site | Google Scholar
B. M. P. Gowd and P. D. Thompson, “Effect of female sex on cardiac arrhythmias,” Cardiology in Review, vol. 20, no. 6, pp. 297–303, 2012.
View at: Publisher Site | Google Scholar
K. Wang, Z.-Q. Lin, B. Long, J.-H. Li, J. Zhou, and P.-F. Li, “Cardiac hypertrophy is positively regulated by microRNA miR-23a,” The Journal of Biological Chemistry, vol. 287, no. 1, pp. 589–599, 2011.
View at: Publisher Site | Google Scholar
L.-Y. Sun, N. Wang, T. Ban et al., “MicroRNA-23a mediates mitochondrial compromise in estrogen deficiency-induced concentric remodeling via targeting PGC-1α,” Journal of Molecular and Cellular Cardiology, vol. 75, pp. 1–11, 2014.
View at: Publisher Site | Google Scholar
L. Goedeke, N. Rotllan, C. M. Ramírez et al., “miR-27b inhibits LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels in mice,” Atherosclerosis, vol. 243, no. 2, pp. 499–509, 2015.
View at: Publisher Site | Google Scholar
S. Dolz, D. Górriz, J. I. Tembl et al., “Circulating microRNAs as novel biomarkers of stenosis progression in asymptomatic carotid stenosis,” Stroke, vol. 48, no. 1, pp. 10–16, 2017.
View at: Publisher Site | Google Scholar
J. Lin, L. Wang, J. Gao, and S. Zhu, “MiR-203 inhibits estrogen-induced viability, migration and invasion of estrogen receptor α-positive breast cancer cells,” Experimental and Therapeutic Medicine, vol. 14, no. 3, pp. 2702–2708, 2017.
View at: Publisher Site | Google Scholar
C. J. Nicholson, F. Seta, S. Lee, and K. G. Morgan, “MicroRNA-203 mimics age-related aortic smooth muscle dysfunction of cytoskeletal pathways,” Journal of Cellular and Molecular Medicine, vol. 21, no. 1, pp. 81–95, 2017.
View at: Publisher Site | Google Scholar
H. Li, J. Zhou, X. Wei et al., “miR-144 and targets, c-fos and cyclooxygenase-2 (COX2), modulate synthesis of PGE2 in the amnion during pregnancy and labor,” Scientific Reports, vol. 6, no. 1, article 27914, 2016.
View at: Publisher Site | Google Scholar
X. Wang, H. Zhu, X. Zhang et al., “Loss of the miR-144/451 cluster impairs ischaemic preconditioning-mediated cardioprotection by targeting Rac-1,” Cardiovascular Research, vol. 94, no. 2, pp. 379–390, 2012.
View at: Publisher Site | Google Scholar
A. Csiszar, T. Gautam, D. Sosnowska et al., “Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats,” American Journal of Physiology. Heart and Circulatory Physiology, vol. 307, no. 3, pp. H292–H306, 2014.
View at: Publisher Site | Google Scholar
C. M. Ramírez, N. Rotllan, A. V. Vlassov et al., “Control of cholesterol metabolism and plasma high-density lipoprotein levels by microRNA-144,” Circulation Research, vol. 112, no. 12, pp. 1592–1601, 2013.
View at: Publisher Site | Google Scholar
M. P. Corcoran, A. H. Lichtenstein, M. Meydani, A. Dillard, E. J. Schaefer, and S. Lamon-Fava, “The effect of 17β-estradiol on cholesterol content in human macrophages is influenced by the lipoprotein milieu,” Journal of Molecular Endocrinology, vol. 47, no. 1, pp. 109–117, 2011.
View at: Publisher Site | Google Scholar
H. S. Cheng, N. Sivachandran, A. Lau et al., “MicroRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways,” EMBO Molecular Medicine, vol. 5, no. 7, pp. 1017–1034, 2013.
View at: Publisher Site | Google Scholar
F. Olivieri, R. Lazzarini, R. Recchioni et al., “MiR-146a as marker of senescence-associated pro-inflammatory status in cells involved in vascular remodelling,” Age, vol. 35, no. 4, pp. 1157–1172, 2013.
View at: Publisher Site | Google Scholar
M. Vasa-Nicotera, H. Chen, P. Tucci et al., “miR-146a is modulated in human endothelial cell with aging,” Atherosclerosis, vol. 217, no. 2, pp. 326–330, 2011.
View at: Publisher Site | Google Scholar
X. Zhang, G. Azhar, and J. Y. Wei, “The expression of microRNA and microRNA clusters in the aging heart,” PLoS One, vol. 7, no. 4, article e34688, 2012.
View at: Publisher Site | Google Scholar
F. Olivieri, L. Spazzafumo, G. Santini et al., “Age-related differences in the expression of circulating microRNAs: miR-21 as a new circulating marker of inflammaging,” Mechanisms of Ageing and Development, vol. 133, no. 11-12, pp. 675–685, 2012.
View at: Publisher Site | Google Scholar
Y. Zhang, Y. J. Liu, T. Liu, H. Zhang, and S. J. Yang, “Plasma microRNA-21 is a potential diagnostic biomarker of acute myocardial infarction,” European Review for Medical and Pharmacological Sciences, vol. 20, no. 2, pp. 323–329, 2016.
View at: Google Scholar
T. Thum, C. Gross, J. Fiedler et al., “MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts,” Nature, vol. 456, no. 7224, pp. 980–984, 2008.
View at: Publisher Site | Google Scholar
J. Zhou, K. C. Wang, W. Wu et al., “MicroRNA-21 targets peroxisome proliferators-activated receptor-α in an autoregulatory loop to modulate flow-induced endothelial inflammation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 25, pp. 10355–10360, 2011.
View at: Publisher Site | Google Scholar
R. Ji, Y. Cheng, J. Yue et al., “MicroRNA expression signature and antisense-mediated depletion reveal an essential role of microRNA in vascular neointimal lesion formation,” Circulation Research, vol. 100, no. 11, pp. 1579–1588, 2007.
View at: Publisher Site | Google Scholar
N. S. Wickramasinghe, T. T. Manavalan, S. M. Dougherty, K. A. Riggs, Y. Li, and C. M. Klinge, “Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells,” Nucleic Acids Research, vol. 37, no. 8, pp. 2584–2595, 2009.
View at: Publisher Site | Google Scholar
A. Luchner, U. Bröckel, M. Muscholl et al., “Gender-specific differences of cardiac remodeling in subjects with left ventricular dysfunction: a population-based study,” Cardiovascular Research, vol. 53, no. 3, pp. 720–727, 2002.
View at: Publisher Site | Google Scholar
R. A. Boon, K. Iekushi, S. Lechner et al., “MicroRNA-34a regulates cardiac ageing and function,” Nature, vol. 495, no. 7439, pp. 107–110, 2013.
View at: Publisher Site | Google Scholar
T. Ito, S. Yagi, and M. Yamakuchi, “MicroRNA-34a regulation of endothelial senescence,” Biochemical and Biophysical Research Communications, vol. 398, no. 4, pp. 735–740, 2010.
View at: Publisher Site | Google Scholar
I. Badi, I. Burba, C. Ruggeri et al., “MicroRNA-34a induces vascular smooth muscle cells senescence by SIRT1 downregulation and promotes the expression of age-associated pro-inflammatory secretory factors,” The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, vol. 70, no. 11, pp. 1304–1311, 2015.
View at: Publisher Site | Google Scholar
B. C. Bernardo, X. M. Gao, C. E. Winbanks et al., “Therapeutic inhibition of the miR-34 family attenuates pathological cardiac remodeling and improves heart function,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 43, pp. 17615–17620, 2012.
View at: Publisher Site | Google Scholar
S. Nanni, A. Aiello, A. Re et al., “Estrogen-dependent dynamic profile of eNOS-DNA associations in prostate cancer,” PLoS One, vol. 8, no. 5, article e62522, 2013.
View at: Publisher Site | Google Scholar
B. C. Bernardo, J. Y. Y. Ooi, A. Matsumoto et al., “Sex differences in response to miRNA-34a therapy in mouse models of cardiac disease: identification of sex-, disease- and treatment-regulated miRNAs,” The Journal of Physiology, vol. 594, no. 20, pp. 5959–5974, 2016.
View at: Publisher Site | Google Scholar
V. Jazbutyte, J. Fiedler, S. Kneitz et al., “MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart,” Age, vol. 35, no. 3, pp. 747–762, 2013.
View at: Publisher Site | Google Scholar
S. K. Gupta, A. Foinquinos, S. Thum et al., “Preclinical development of a microRNA-based therapy for elderly patients with myocardial infarction,” Journal of the American College of Cardiology, vol. 68, no. 14, pp. 1557–1571, 2016.
View at: Publisher Site | Google Scholar
L. Wang, Z. P. Tang, W. Zhao et al., “MiR-22/Sp-1 links estrogens with the up-regulation of cystathionine γ-lyase in myocardium, which contributes to estrogenic cardioprotection against oxidative stress,” Endocrinology, vol. 156, no. 6, pp. 2124–2137, 2015.
View at: Publisher Site | Google Scholar
J. Schweisgut, C. Schutt, S. Wust et al., “Sex-specific, reciprocal regulation of ERα and miR-22 controls muscle lipid metabolism in male mice,” The EMBO Journal, vol. 36, no. 9, pp. 1199–1214, 2017.
View at: Publisher Site | Google Scholar
S. Banerjee, H. Cui, N. Xie et al., “miR-125a-5p regulates differential activation of macrophages and inflammation,” The Journal of Biological Chemistry, vol. 288, no. 49, pp. 35428–35436, 2013.
View at: Publisher Site | Google Scholar
A. J. Murphy, P. M. Guyre, and P. A. Pioli, “Estradiol suppresses NF-κB activation through coordinated regulation of let-7a and miR-125b in primary human macrophages,” Journal of Immunology, vol. 184, no. 9, pp. 5029–5037, 2010.
View at: Publisher Site | Google Scholar
P. Che, J. Liu, Z. Shan et al., “miR-125a-5p impairs endothelial cell angiogenesis in aging mice via RTEF-1 downregulation,” Aging Cell, vol. 13, no. 5, pp. 926–934, 2014.
View at: Publisher Site | Google Scholar

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Copyright © 2018 Daniel Pérez-Cremades et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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