Next Article in Journal
Inhibiting Skp2 E3 Ligase Suppresses Bleomycin-Induced Pulmonary Fibrosis
Next Article in Special Issue
The Role of the Estrogen Pathway in the Tumor Microenvironment
Previous Article in Journal
LncRNA HOTTIP-Mediated HOXA11 Expression Promotes Cell Growth, Migration and Inhibits Cell Apoptosis in Breast Cancer
Previous Article in Special Issue
Natural Anti-Estrogen Receptor Alpha Antibodies Able to Induce Estrogenic Responses in Breast Cancer Cells: Hypotheses Concerning Their Mechanisms of Action and Emergence
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 19
Issue 2
10.3390/ijms19020473
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

miRNA as a New Regulatory Mechanism of Estrogen Vascular Action

by
Daniel Pérez-Cremades
1,2,
Ana Mompeón
1,2,
Xavier Vidal-Gómez
1,2,
Carlos Hermenegildo
1,2 and
Susana Novella
1,2,*
1
Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, 46010 Valencia, Spain
2
INCLIVA Biomedical Research Institute, 46010 Valencia, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(2), 473; https://doi.org/10.3390/ijms19020473
Submission received: 22 December 2017 / Revised: 31 January 2018 / Accepted: 1 February 2018 / Published: 6 February 2018
(This article belongs to the Special Issue Molecular Pathways of Estrogen Receptor Action)
Browse Figures
Versions Notes

Abstract

:
The beneficial effects of estrogen on the cardiovascular system have been reported extensively. In fact, the incidence of cardiovascular diseases in women is lower than in age-matched men during their fertile stage of life, a benefit that disappears after menopause. These sex-related differences point to sexual hormones, mainly estrogen, as possible cardiovascular protective factors. The regulation of vascular function by estrogen is mainly related to the maintenance of normal endothelial function and is mediated by both direct and indirect gene transcription through the activity of specific estrogen receptors. Some of these mechanisms are known, but many remain to be elucidated. In recent years, microRNAs have been established as non-coding RNAs that regulate the expression of a high percentage of protein-coding genes in mammals and are related to the correct function of human physiology. Moreover, within the cardiovascular system, miRNAs have been related to physiological and pathological conditions. In this review, we address what is known about the role of estrogen-regulated miRNAs and their emerging involvement in vascular biology.

Graphical Abstract

1. Introduction

Estrogen is involved in many physiological processes, including sexual development and reproduction, regulation of skeletal homeostasis, lipid and carbohydrate metabolism, electrolyte balance, central nervous system function (including cognition and behavior), and cardiovascular system regulation [1,2]. In addition to its physiological relevance, the effects of estrogen (or its absence) on target tissues are related to the development of numerous diseases, which include various types of well-known hormone-dependent cancers including breast, ovarian, endometrial, and prostate cancer, among others. However, estrogen is also implicated in the progression of osteoporosis, neurodegenerative diseases, metabolic disorders (insulin resistance and obesity), autoimmune diseases (lupus erythematosus, multiple sclerosis, and rheumatoid arthritis), endometriosis, and cardiovascular diseases [3].
Sex differences in cardiovascular diseases have been extensively reported [4], suggesting that sex hormones have an important influence on the cardiovascular system. Indeed, statistical data have shown that women develop cardiovascular disease 7–10 years later than men [5]. In addition, epidemiological studies have provided evidence that cardi ovascular diseases are more frequent in men than in premenopausal women of the same age. However, during the fifth decade of a woman’s life, the decrease in estrogen levels that occurs in menopause is accompanied by an increase in the incidence of cardiovascular diseases [6,7], suggesting that estrogen plays a beneficial role in cardiovascular system.
Based on the beneficial role of estrogen, hormonal replacement therapies (HRT) have been used in postmenopausal women with controversial findings [8,9]. The current consensus on HRT indicates that the vascular protective effects of estrogen depend on the onset of treatment after menopause, which has been recently reviewed in depth elsewhere [10]. The phenomenon, referred to as the “timing hypothesis”, postulates that the beneficial effects of hormonal replacement in the prevention of cardiovascular disease may occur only when hormonal supplementation is initiated before the detrimental effects that aging has on the cardiovascular system have become established [11]. In this regard, it has been reported that age moderates the vasodilatory [12] and anti-inflammatory [13] effects that estrogen have on vascular tissue in postmenopausal women.
Estrogen can modulate the cardiovascular system by acting directly on vascular cells or indirectly by systemic effects. Endothelial cells, vascular smooth muscle cells (VSMCs), and cardiomyocytes are estrogen targets because they express estrogen receptors (ER) [14]. In addition, ER expression described in monocytes, macrophages, and dendritic cells suggests that modulation of inflammatory processes, a key event in the initiation and development of cardiovascular diseases, may also be estrogen-dependent [15,16].
ERs function through two predominant mechanisms. In the “classical” mechanism, estrogen diffuses into the cell and binds the ERs, creating a complex that then binds to specific DNA motifs called estrogen response elements (EREs) in the promoter region of estrogen-responsive genes [17]. Classical mechanisms are mediated by two main ER isoforms, ERα and ERβ, which form homo- or heterodimers before binding to EREs, and which induce changes in gene expression. Several studies have provided evidence that ERα and ERβ have different physiological functions [18]. Indeed, these subtypes can have opposing gene-expression regulatory effects [19,20] and also have redundant mediatory roles [21,22]. In addition, estrogen signaling is selectively regulated by the relative balance between ERα and ERβ expression in target organs [23], although studies using ERα and ERβ knockout mice revealed that the beneficial effects estrogen has on the vascular system are mainly mediated by ERα [24,25].
Besides their classic genomic action, ERs can also trigger faster responses (in minutes) through plasma membrane receptors. Indeed, ERα and ERβ are present in plasma membranes and other cytoplasmic organelles such as mitochondria and endoplasmic reticulum membranes [26]. In addition, the recently described G protein-coupled ER (GPER) is also expressed in vascular tissues [27]. Indeed, many of the beneficial effects of estrogen seen in human and animal models, such as reduced myocardial pro-inflammatory cytokine expression, inhibition of VSMC proliferation, and nitric oxide (NO)-dependent vasodilation [28], have been recently attributed to the presence of GPER in the cardiovascular system.

2. Role of Estrogen in Vascular Physiology

As described above, vascular tissues are targets for sex hormones because specific receptors are expressed in both endothelial cells and VSMCs [14] and clinical and experimental data have demonstrated that estrogen has beneficial effects at the cardiovascular level [29,30]. In general, these protective effects have been attributed to their role in increasing arterial vasodilation and inhibiting inflammatory processes, which, in turn, prevent the development of atherosclerosis [6]. Moreover, estrogen can also indirectly influence plaque progression by modulating systemic lipid metabolism [31] and oxidative status [32].
The regulation of vascular reactivity by estrogen is mainly related to the maintenance of normal endothelial function [33]. Indeed, enhanced acetylcholine-induced vasodilation mediated by NO release in arteries isolated from estrogen-treated ovariectomized rabbits was one of the first evidence indicating the role of estrogen in vascular tone [34]. In endothelial cells, the modulation of NO bioavailability by estrogen has been extensively studied and is attributed to both genomic and non-genomic effects [35,36,37]. In addition to NO, the action of estrogen has also been implicated in the release of other endothelial-derived molecules such as prostacyclin [38] and angiotensin (Ang) 1–7 [39] and a decrease in endothelin-1 bioavailability [40] and Ang II receptor type 1 expression [41], thus reducing vasoconstriction and promoting vasodilation.
Besides their effect on vasomotor regulation, the anti-inflammatory responses induced by estrogen have been described in in vitro assays as well as in different vascular-injury models [42,43,44,45]. In this regard, estrogen reduces cell adhesion molecule expression in endothelial cells exposed to pro-inflammatory stimuli [46,47], and significantly decreases the cytokine-induced adhesion of monocytes to endothelium [48,49]. Moreover, the modulation of neutrophil chemotaxis [44] and leukocyte infiltration [45] by estradiol has been described in rat carotid arteries after acute injury. Estrogen treatment after rat carotid artery damage [50] also attenuates neointima formation by increasing endothelial cell growth and decreasing VSMC proliferation.
Estrogen also participates in the regulation of lipid accumulation in the vascular wall by modulating the plasma lipid profile and inhibiting the direct action of lipids on the vascular system. On the one hand, estrogen reduces the level of circulating cholesterol [51] and the rate of conversion of hepatic low-density lipoprotein (LDL) into bile acids [52] while on the other, it increases high-density lipoprotein (HDL) levels [53]. In addition, estrogen is associated with reduced lipid loading in human monocyte-derived macrophages [54] and VSMCs [55], preventing foam cell formation. Furthermore, estradiol exposure inhibits cellular permeability [56] and apoptosis [57] in LDL-exposed endothelial cells. Finally, estrogen attenuates the oxidative stress-mediated increase in LDL modifications, which accelerates lipid accumulation in arterial walls [58].
Although the antioxidant properties of steroids were first attributed to their phenolic structure [59], estrogen can also modulate antioxidant enzyme expression [60,61]. For instance, estradiol attenuates Ang II-induced superoxide production by increasing superoxide dismutase activity and protein expression in VSMCs [60] and endothelial cells [61]. Estradiol also reduces superoxide production by inhibiting nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression, thus reducing adhesion molecule and cytokine expression in VSMCs [62] and, in an experimental murine model of menopause, by reverting cyclooxygenase (COX) 2-dependent superoxide production in aortic tissue [63].

3. miRNA as Epigenetic Regulatory Mechanism

As previously described, classical regulation of physiological processes by estradiol includes estrogen signaling induced by direct and indirect target gene transcription. However, epigenetic mechanisms have recently emerged as another important source of gene expression regulation and are being widely studied. At the molecular level, epigenetics is based on three main pathways: (1) DNA methylation; (2) histone density, variants, and post-translational modifications; and (3) RNA-based mechanisms [64]. Together, these pathways are characterized by their ability to influence gene expression without changing the DNA sequence and many have been established as fundamental determinants of cardiovascular health and disease [65,66].
There is some evidence that epigenetic estrogen-regulation mechanisms are implicated in the regulation of cardiovascular function. For example, genes encoding ERs are more methylated (denoting the suppression of estrogenic activity) in atherosclerotic plaques compared to non-plaque regions in vascular tissues [67,68], thus suggesting that epigenetic ER inhibition plays an important role in atherosclerosis formation. On the other hand, histone modifications and chromatin remodeling also likely have estrogen-dependent effects on the vasculature [69,70]. Indeed, divergent estrogen-dependent gene expression in endothelial cells and VSMCs is linked to differential target-gene promoter histone acetylation [69]. Moreover, the vascular dysfunction prevented by estradiol is associated with histone 3 acetylation in a post-menopausal metabolic syndrome experimental model [70]. Finally, RNA-based epigenetic gene-expression regulatory mechanisms mediated by sequence-specific interactions have more recently been described and are our main focus in this review.
Regulatory non-coding RNA can be classified depending on the RNA length. Long non-coding RNA (lncRNA) is a heterogenic class of RNA that includes intergenic lncRNA, antisense transcripts, and enhancer RNA. All of them are described as non-protein-coding transcripts larger than 200 nucleotides (nt) so as to differentiate them from small non-coding RNAs [71]. These include microRNA (miRNA), small interfering RNA (siRNA), and Piwi-interacting RNA (piRNA), and are defined as small (20–30 nt) RNAs, which are associated with Argonaute (AGO) family proteins [72]. Moreover, a new class of non-coding RNAs derived from sequences located adjacent to miRNAs, termed miRNA offset RNA (moR), has been described [73]. Although moRs were first considered a by-product of miRNA biogenesis, recent studies have provided evidence that are biologically active and can alter gene expression to regulate cell proliferation in VSMCs [74].
miRNAs about 20–22 nt long are the dominant class of small non-coding RNA in most tissues and are derived from nuclear transcripts with characteristic stem–loop structures (pri-miRNAs). The first step in miRNA biosynthesis is pri-miRNA cleavage, mediated by a processing complex comprising the RNase III Drosha and DiGeorge syndrome critical region 8 (DGCR8), also known as the microprocessor complex. Nuclear processing involves cropping the stem–loop to release a small hairpin-shaped RNA (pre-miRNA), which is then transported into the cytoplasm through exportin 5 where maturation can be completed. The second processing step is mediated by the RNase III, DICER1, which cleaves the pre-miRNA into 22-nt miRNA duplexes. Usually, one strand from the cleavage products remains as a mature miRNA due to a selective process that depends on thermodynamic stability. Finally, RNA generated is loaded into an AGO protein to form the effector RNA-induced silencing complex (RISC) along with other component such as TAR RNA-binding protein (TRBP) or protein kinase R-activating protein (PACT). miRNAs function as a guide by base pairing with their target messenger RNAs (mRNAs), while AGO proteins recruit factors that induce this translational repression; miRNA-binding sites are usually located at the 3′-untranslated region (UTR) of the target mRNA [75]. Figure 1 shows a schematic of the miRNA biosynthesis pathway along with most of the relevant implicated molecules.
Although no specific research has so far focused on the influence estrogen might exert on miRNA biosynthesis in vascular tissues, our group’s work on human endothelial cells treated with estradiol produced mRNA microarray data revealing the deregulation of key miRNA biosynthesis pathway genes [76]. Our data shows DGCR8 upregulation and DICER1 and AGO-2 downregulation in estradiol-treated cells (Table 1), suggesting that estrogen regulates endothelial miRNA production machinery.
In addition to data obtained in estradiol-treated endothelial cells, the relationship between estrogen action and miRNA biosynthesis has been extensively described in breast cancer samples, where differences in key miRNA-processing genes have been observed between ER+ and ER− breast cancer cells [77,78]. Specifically, the expression of DICER1, DGCR8, and DROSHA was higher, and that of AGO-2 lower, in ER+ breast tumors. In addition, of the miRNA processing genes this group studied, only DICER1 contains an ERα binding site in its regulatory region [79]. Indeed, miRNAs that are differentially expressed between ERα− and ERα+ breast cancer cells negatively control DICER1 expression [80], suggesting that a regulatory loop exists between ERs and miRNAs. In addition, other studies suggest that ERs interact with DROSHA to modulate its activity in breast cancer cells [81] and that a significant increase in Exportin-5 mRNA is induced in the mouse uterus by the action of estrogen [82].
Specific miRNAs target ERs and could therefore act as important ER-dependent gene expression modulators. Indeed, some estrogen-induced miRNAs such as miR-18a, miR-19b, and miR-20b target and regulate ERα expression, thus forming a negative feedback loop [83]. Other miRNAs, including miR-18a, miR-22, miR-206, and miR-221/222 have also been implicated in ERα targeting [84]. Finally, the only miRNAs identified as targeting ERβ [85] and GPER [86], respectively, are miR-92 and miR-424.

4. Vascular miRNA and Estrogen Action

The importance of miRNAs in vascular biology was first observed in 2005 by Yang et al., who described impaired vascular formation in DICER1 knockout mice [87]. In endothelial cells, DICER1 knockdown resulted in impaired proliferation and vessel formation, as well as altered expression of key proteins implicated in vascular tone regulation and angiogenesis, such as vascular endothelial growth factor receptor 2 (VEGFR), interleukin 8 (IL-8), and endothelial NO synthases (eNOS) [88,89], thus suggesting a role of miRNAs production in endothelial and vascular function.
Sex differences in miRNA expression have also been described in different physiological and pathological conditions [90,91], providing evidence for a role for sex hormones in miRNA regulation. Nevertheless, the relationship between sex-dependent miRNA expression and cardiovascular diseases has so far been little explored [90], although regulation of miRNA expression by estrogen was observed in different cell types and tissues [92]. In addition, the role of estrogen in the circulating miRNA profile has been described in both ovariectomized rats and postmenopausal women receiving hormone replacement treatments [93,94]; based on these results, different authors have proposed using these miRNA profiles as possible biomarkers for pathologies involving estrogen.

4.1. Estrogen-Dependent miRNA and Cardiovascular Function

Different studies have proposed that estrogen exerts its vascular protective effects, at least in part, via miRNA activity. For instance, the role of estrogen-induced miRNAs in heart tissue, VSMCs, and endothelial cells has been described; Table 2 summarizes the main miRNAs involved in the action of estrogen at cardiovascular level. Additionally, sex-dimorphic miRNA expression in heart tissue from males versus females has been noted, including for miR-222. As previously mentioned, this miRNA is involved in ERα regulation [84] and is implicated in modulating eNOS expression in cardiomyocytes by directly inhibiting the transcription factor ets-1 [95]. These results suggest that estrogen plays a role in regulating both the miRNA expression profile in cardiac tissues as well as the key molecules involved in cardiac function. In addition, miR-21, miR-24, miR-27a/b, and miR-106a/b were among the sex-specific miRNAs expressed via ERβ modulation in a murine model of pressure overload-induced cardiac fibrosis [96] and could help explain the differences in adaptation to pressure overload and vascular remodeling observed between women and men [97].
Important roles for miR-23a and miR-22 have also been described in cardiac function involving the action of estrogen. Specifically, miR-23a has regulatory regions containing ERα binding sites and plays a protective role in estrogen deficiency-induced cardiac gap-junction damage in rats [98]. The authors showed that estradiol inhibits miR-23-dependent downregulation of connexin 43 in a menopausal rat model, and provide new mechanisms of post-menopause-related arrhythmia [99]. In addition to its role in cardiac function, miR-23a levels also differ in males and females after cerebral ischemia and are related to accelerating apoptosis by regulating X-linked inhibitor of apoptosis (XIAP) expression and XIAP-caspase complex formation [100]. Thus, this evidence provides new insights into the molecular mechanisms underlying the sex-dependent responses observed following stroke [101]. Moreover, miR-22 provides estrogenic cardioprotection in female rats by controlling myocardial oxidative stress [102]. This same study also described a reciprocal feedback loop between ERα and miR-22, suggesting that estrogen action is closely regulated via post-transcriptional control of ERα expression. Similarly, the sex-specific regulation of miR-22 processing in muscle lipid metabolism has also recently been described and may contribute to understanding the well-described differences in muscle metabolism and body weight between males and females [103].
Considering vascular tissue, some studies show that VSMC proliferation is affected by miRNAs and highlight their potential as therapeutic agents in the treatment of proliferative cardiovascular diseases. In the case of mouse aorta, miR-203 contributes to the inhibition of VSMC proliferation because its upregulation is ER-dependent [104]. Estradiol induces miR-143 and miR-145 expression in pulmonary artery VSMCs via specific ER binding sites located in their promoter regions [105]. Moreover, estradiol-treated VSMCs secrete exosomes enriched with miR-143 and miR-145 which regulate VSMC-endothelium crosstalk in pulmonary arterial hypertension [105].
Focusing on the endothelium, microarrays were recently used to reveal that physiological (1 nmol/L) estradiol concentrations induce changes in the miRNA expression profile of endothelial cells [106]; among these, the miRNAs with the strongest differential expression were miR-30b-5p, miR-487a-5p, miR-4710, miR-501-3p, miR-378h, and miR-1244. Functional analysis using bioinformatic tools revealed that estradiol-modulated miRNAs were associated with key molecular pathways such as extracellular signaling from signal-regulated kinase/mitogen activated protein kinase (ERK/MAPK), integrins, and actin cytoskeleton signaling, which are important pathways in the regulation of vascular physiology in health and disease [106]. Additionally, most validated estradiol-regulated miRNAs were modulated by ERα, and to a lesser extent, by ERβ and GPER [106], thus lending weight to the idea that ERα plays a crucial role in estradiol-dependent effects on vascular tissues. On the other hand, estradiol is also implicated in the increased miR-126-3p expression observed in endothelial cells, resulting in increased cell migration, proliferation, and tube formation and decreased monocyte adhesion [107].
As previously described, estrogen plays a key role in modulating the immune system and this is probably the underlying cause of the sex differences observed in the inflammatory processes of atherosclerosis [108]. For instance, estradiol is involved in nuclear factor-kB (NF-kB) activity inhibition by regulating let-7a and miR-125b expression in stimulated macrophages [109]. Moreover, specific estradiol-regulated miRNAs—miR-146a and miR-223—have been described as key regulators of lipopolysaccharide-induced interferon-gamma (IFNγ) in lymphocytes [110]. Therefore, selective miRNA expression regulated by estrogen in immune cells could also be involved in the sex dimorphism observed in vascular diseases.

4.2. miRNA and Hormone Replacement Therapy

The use of HRT has recently been associated with the miRNA content of circulating exosomes in women [94]. In addition, the miRNA-mediated effects of this type of estrogenic therapy appear to improve the parameters of some disorders such as osteoporosis and sarcopenia and help to reduce the inflammation markers associated with these phenomena in postmenopausal women using HRT.
Although the relationship between estrogen levels and osteoporosis has been established for decades [113], changes in the miRNA expression profile in bone tissue from ovariectomy-induced osteoporotic mice and in postmenopausal women have recently been described [93,112]. Specifically, from among the miRNAs that are differentially expressed in estrogen-depleted mice, miR-127 and miR-136 negatively regulate bone mass [112], whereas miR-30b-5p may be a suitable serum biomarker for osteoporosis and osteopenia in postmenopausal women [93]. Moreover, suppressing the expression of miR-182 and miR-223, both implicated in regulating the insulin/insulin-like growth factor (IGF-1) pathway, in the skeletal muscle of postmenopausal women using HRT plays a central role in muscle mass regulation [111]. Therefore, the identification of estrogen-regulated miRNAs could be used as possible therapeutic targets to provide new insights into aging-related disorders such as sarcopenia. In addition, a study in monozygotic twin pairs revealed a relationship between changes in serum inflammatory markers and inflammatory-related miRNAs such as miR-21 and miR-146a, in postmenopausal women using HRT [114]. Thus, estrogen-sensitive miRNAs could be used as potential biomarkers for specific physiological deteriorations associated with female aging.
In another study, in premenopausal women and their monozygotic postmenopausal twins using estrogenic HRT, other circulating miRNAs included in exosomes, such as miR-148a-3p, miR-27-3p, miR-28-3p, miR-30a-5p, miR-106b-5p, and miR-126-5p were associated with serum estradiol levels [94]. miR-148a is related to regulation of plasma LDL/HDL ratio by directly regulating hepatic LDL receptor (LDLR) [115]. This effect could be related to the previously demonstrated effects of estrogen on circulating cholesterol levels as estrogen is implicated in the reduction of circulating cholesterol by increasing LDLR expression [116]. Another estrogen-related miRNA, miR-27, is also implicated in LDLR expression without producing changes in plasma cholesterol levels [117]; this miRNA is also related to angiogenic processes [89] and was recently suggested as a biomarker for stenotic progression in asymptomatic carotid stenosis [118]. In this regard, there are sex-related differences in patients with this pathology [119] that may be partly related to the role of estrogen-regulated miRNAs. Therefore, a better understanding of the mechanisms underlying these processes could improve new sex-specific therapeutic approaches.
MiR-106b-5p decreases tumor necrosis factor (TNF) α-induced apoptosis by repressing phosphatase and tensin homolog (PTEN)-caspase activity in vascular endothelial cells [120]. Moreover, these effects correlate with the repressive effects that estrogen have on PTEN and apoptosis [121,122]. miR-126-5p is required to produce correct vascular integrity and is key in angiogenic processes [123,124] and also decreases leukocyte-endothelium interactions by suppressing vascular cell adhesion molecule (VCAM)-1 [125]. In line with the aforementioned studies, miR-126-5p is among the estradiol-regulated miRNAs present in endothelial cells [107]. Therefore, the estradiol-sensitive miRNAs described could provide insight into the mechanisms by which estrogen modulates important endothelial processes such as apoptosis or angiogenesis to provide correct vascular physiology.

5. Conclusions

The differences observed in cardiovascular diseases between the sexes attribute a protective role to estrogen, which is mediated through the regulation of transcription processes and, in turn, cellular physiology. Indeed, sex-biased gene expression in the cardiovascular system and mediated by estrogen has already been reported. It is estimated that miRNAs regulate the expression of approximately 30% of all protein-coding genes in mammals, implying their importance in correctly functioning human physiology, including that of the cardiovascular system. However, although there is increasing evidence to establish epigenetic mechanisms, including miRNAs, as crucial regulators of vascular function, the role of miRNAs in estrogen-mediated vascular functions must still be elucidated. Therefore, future research focused on characterizing the role of specific estradiol-mediated miRNAs involved in vascular function will be required to provide new knowledge about how the levels of sex hormones can contribute to sex-related differences in cardiovascular diseases.

Acknowledgments

This work was supported by Spanish Ministerio de Economía y Competitividad, Instituto de Salud Carlos III—FEDER-ERDF (grants FIS PI13/00617 and PI16/00229). Ana Mompeón is a “Formación de Profesorado Universitario” fellow (grant number FPU13/02235 Spanish Ministerio de Educación, Cultura y Deporte).

Author Contributions

All authors wrote and revised the manuscript, and agreed to be accountable for all aspects of this study.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Burns, K.A.; Korach, K.S. Estrogen receptors and human disease: An update. Arch. Toxicol. 2012, 86, 1491–1504. [Google Scholar] [CrossRef] [PubMed]
  2. Vrtacnik, P.; Ostanek, B.; Mencej-Bedrac, S.; Marc, J. The many faces of estrogen signaling. Biochem. Med. 2014, 24, 329–342. [Google Scholar] [CrossRef] [PubMed]
  3. Deroo, B.J.; Korach, K.S. Estrogen receptors and human disease. J. Clin. Investig. 2006, 116, 561–570. [Google Scholar] [CrossRef] [PubMed]
  4. Mendelsohn, M.E.; Karas, R.H. Molecular and Cellular Basis of Cardiovascular Gender Differences. Science 2005, 308, 1583–1587. [Google Scholar] [CrossRef] [PubMed]
  5. Hayward, C.S.; Kelly, R.P.; Collins, P. The roles of gender, the menopause and hormone replacement on cardiovascular function. Cardiovasc. Res. 2000, 46, 28–49. [Google Scholar] [CrossRef]
  6. Mendelsohn, M.E.; Karas, R.H. The protective effects of estrogen on the cardiovascular system. N. Engl. J. Med. 1999, 340, 1801–1811. [Google Scholar] [CrossRef] [PubMed]
  7. Mikkola, T.S.; Gissler, M.; Merikukka, M.; Tuomikoski, P.; Ylikorkala, O. Sex differences in age-related cardiovascular mortality. PLoS ONE 2013, 8, e63347. [Google Scholar] [CrossRef] [PubMed]
  8. Simon, J.A.; Hsia, J.; Cauley, J.A.; Richards, C.; Harris, F.; Fong, J.; Barrett-Connor, E.; Hulley, S.B. Postmenopausal hormone therapy and risk of stroke: The Heart and Estrogen-progestin Replacement Study (HERS). Circulation 2001, 103, 638–642. [Google Scholar] [CrossRef] [PubMed]
  9. Rossouw, J.E.; Prentice, R.L.; Manson, J.E.; Wu, L.; Barad, D.; Barnabei, V.M.; Ko, M.; LaCroix, A.Z.; Margolis, K.L.; Stefanick, M.L. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007, 297, 1465–1477. [Google Scholar] [CrossRef] [PubMed]
  10. Lobo, R.A. Hormone-replacement therapy: Current thinking. Nat. Rev. Endocrinol. 2017, 13, 220–231. [Google Scholar] [CrossRef] [PubMed]
  11. Clarkson, T.B.; Melendez, G.C.; Appt, S.E. Timing hypothesis for postmenopausal hormone therapy: Its origin, current status, and future. Menopause 2013, 20, 342–353. [Google Scholar] [CrossRef] [PubMed]
  12. Sherwood, A.; Bower, J.K.; McFetridge-Durdle, J.; Blumenthal, J.A.; Newby, L.K.; Hinderliter, A.L. Age moderates the short-term effects of transdermal 17β-estradiol on endothelium-dependent vascular function in postmenopausal women. Arterioscler. Thromb. Vasc. Biol. 2007, 27, 1782–1787. [Google Scholar] [CrossRef] [PubMed]
  13. Novella, S.; Heras, M.; Hermenegildo, C.; Dantas, A.P. Effects of estrogen on vascular inflammation: A matter of timing. Arterioscler. Thromb. Vasc. Biol. 2012, 32, 2035–2042. [Google Scholar] [CrossRef] [PubMed]
  14. Khalil, R.A. Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease. Biochem. Pharmacol. 2013, 86, 1627–1642. [Google Scholar] [CrossRef] [PubMed]
  15. Härkönen, P.L.; Väänänen, H.K. Monocyte—Macrophage System as a Target for Estrogen and Selective Estrogen Receptor Modulators. Ann. N. Y. Acad. Sci. 2006, 1089, 218–227. [Google Scholar] [CrossRef] [PubMed]
  16. Kovats, S. Estrogen receptors regulate innate immune cells and signaling pathways. Cell. Immunol. 2015, 294, 63–69. [Google Scholar] [CrossRef] [PubMed]
  17. Klinge, C.M. Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res. 2001, 29, 2905–2919. [Google Scholar] [CrossRef] [PubMed]
  18. O’Lone, R.; Knorr, K.; Jaffe, I.Z.; Schaffer, M.E.; Martini, P.G.; Karas, R.H.; Bienkowska, J.; Mendelsohn, M.E.; Hansen, U. 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. Mol. Endocrinol. 2007, 21, 1281–1296. [Google Scholar] [CrossRef] [PubMed]
  19. Lindberg, M.K.; Moverare, S.; Skrtic, S.; Gao, H.; Dahlman-Wright, K.; Gustafsson, J.A.; Ohlsson, C. Estrogen receptor (ER)-β reduces ERα-regulated gene transcription, supporting a “ying yang” relationship between ERα and ERβ in mice. Mol. Endocrinol. 2003, 17, 203–208. [Google Scholar] [CrossRef] [PubMed]
  20. Tsutsumi, S.; Zhang, X.; Takata, K.; Takahashi, K.; Karas, R.H.; Kurachi, H.; Mendelsohn, M.E. Differential regulation of the inducible nitric oxide synthase gene by estrogen receptors 1 and 2. J. Endocrinol. 2008, 199, 267–273. [Google Scholar] [CrossRef] [PubMed]
  21. Lahm, T.; Crisostomo, P.R.; Markel, T.A.; Wang, M.; Wang, Y.; Tan, J.; Meldrum, D.R. Selective estrogen receptor-α and estrogen receptor-β agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide-dependent mechanism. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008, 295, R1486–R1493. [Google Scholar] [CrossRef] [PubMed]
  22. Arias-Loza, P.A.; Hu, K.; Dienesch, C.; Mehlich, A.M.; Konig, S.; Jazbutyte, V.; Neyses, L.; Hegele-Hartung, C.; Heinrich Fritzemeier, K.; Pelzer, T. Both estrogen receptor subtypes, α and β, attenuate cardiovascular remodeling in aldosterone salt-treated rats. Hypertension 2007, 50, 432–438. [Google Scholar] [CrossRef] [PubMed]
  23. Murphy, E.; Steenbergen, C. Estrogen regulation of protein expression and signaling pathways in the heart. Biol. Sex Differ. 2014, 5, 6. [Google Scholar] [CrossRef] [PubMed]
  24. Pare, G.; Krust, A.; Karas, R.H.; Dupont, S.; Aronovitz, M.; Chambon, P.; Mendelsohn, M.E. Estrogen receptor-α mediates the protective effects of estrogen against vascular injury. Circ. Res. 2002, 90, 1087–1092. [Google Scholar] [CrossRef] [PubMed]
  25. Arnal, J.-F.; Lenfant, F.; Metivier, R.; Flouriot, G.; Henrion, D.; Adlanmerini, M.; Fontaine, C.; Gourdy, P.; Chambon, P.; Katzenellenbogen, B.; et al. Membrane and Nuclear Estrogen Receptor α Actions: From Tissue Specificity to Medical Implications. Physiol. Rev. 2017, 97, 1045. [Google Scholar] [CrossRef] [PubMed]
  26. Levin, E.R. Plasma membrane estrogen receptors. Trends Endocrinol. Metab. 2009, 20, 477–482. [Google Scholar] [CrossRef] [PubMed]
  27. Revankar, C.M.; Cimino, D.F.; Sklar, L.A.; Arterburn, J.B.; Prossnitz, E.R. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 2005, 307, 1625–1630. [Google Scholar] [CrossRef] [PubMed]
  28. Prossnitz, E.R.; Barton, M. The G protein-coupled estrogen receptor GPER in health and disease. Nat. Rev. Endocrinol. 2011, 7, 715–726. [Google Scholar] [CrossRef] [PubMed]
  29. Vitale, C.; Mendelsohn, M.E.; Rosano, G.M. Gender differences in the cardiovascular effect of sex hormones. Nat. Rev. Cardiol. 2009, 6, 532–542. [Google Scholar] [CrossRef] [PubMed]
  30. Miller, V.M.; Duckles, S.P. Vascular actions of estrogens: Functional implications. Pharmacol. Rev. 2008, 60, 210–241. [Google Scholar] [CrossRef] [PubMed]
  31. Barton, M. Cholesterol and atherosclerosis: Modulation by oestrogen. Curr. Opin. Lipidol. 2013, 24, 214–220. [Google Scholar] [CrossRef] [PubMed]
  32. Kondo, T.; Hirose, M.; Kageyama, K. Roles of Oxidative Stress and Redox Regulation in Atherosclerosis. J. Atheroscler. Thromb. 2009, 16, 532–538. [Google Scholar] [CrossRef] [PubMed]
  33. Miller, V.M.; Mulvagh, S.L. Sex steroids and endothelial function: Translating basic science to clinical practice. Trends Pharmacol. Sci. 2007, 28, 263–270. [Google Scholar] [CrossRef] [PubMed]
  34. Gisclard, V.; Flavahan, N.A.; Vanhoutte, P.M. α adrenergic responses of blood vessels of rabbits after ovariectomy and administration of 17 β-estradiol. J. Pharmacol. Exp. Ther. 1987, 240, 466–470. [Google Scholar] [PubMed]
  35. Chambliss, K.L.; Shaul, P.W. Estrogen modulation of endothelial nitric oxide synthase. Endocr. Rev. 2002, 23, 665–686. [Google Scholar] [CrossRef] [PubMed]
  36. Novella, S.; Laguna-Fernández, A.; Lázaro-Franco, M.; Sobrino, A.; Bueno-Betí, C.; Tarín, J.J.; Monsalve, E.; Sanchís, J.; Hermenegildo, C. Estradiol, acting through estrogen receptor α, restores dimethylarginine dimethylaminohydrolase activity and nitric oxide production in oxLDL-treated human arterial endothelial cells. Mol. Cell. Endocrinol. 2013, 365, 11–16. [Google Scholar] [CrossRef] [PubMed]
  37. Sobrino, A.; Vallejo, S.; Novella, S.; Lazaro-Franco, M.; Mompeon, A.; Bueno-Beti, C.; Walther, T.; Sanchez-Ferrer, C.; Peiro, C.; Hermenegildo, C. Mas receptor is involved in the estrogen-receptor induced nitric oxide-dependent vasorelaxation. Biochem. Pharmacol. 2017, 129, 67–72. [Google Scholar] [CrossRef] [PubMed]
  38. Sobrino, A.; Oviedo, P.J.; Novella, S.; Laguna-Fernandez, A.; Bueno, C.; Garcia-Perez, M.A.; Tarin, J.J.; Cano, A.; Hermenegildo, C. Estradiol selectively stimulates endothelial prostacyclin production through estrogen receptor-α. J. Mol. Endocrinol. 2010, 44, 237–246. [Google Scholar] [CrossRef] [PubMed]
  39. Mompeón, A.; Lázaro-Franco, M.; Bueno-Betí, C.; Pérez-Cremades, D.; Vidal-Gómez, X.; Monsalve, E.; Gironacci, M.M.; Hermenegildo, C.; Novella, S. Estradiol, acting through ERα, induces endothelial non-classic renin-angiotensin system increasing angiotensin 1–7 production. Mol. Cell. Endocrinol. 2016, 422, 1–8. [Google Scholar] [CrossRef] [PubMed]
  40. Dubey, R.K.; Jackson, E.K.; Keller, P.J.; Imthurn, B.; Rosselli, M. Estradiol metabolites inhibit endothelin synthesis by an estrogen receptor-independent mechanism. Hypertension 2001, 37, 640–644. [Google Scholar] [CrossRef] [PubMed]
  41. Nickenig, G.; Bäumer, A.T.; Grohè, C.; Kahlert, S.; Strehlow, K.; Rosenkranz, S.; Stäblein, A.; Beckers, F.; Smits, J.F.M.; Daemen, M.J.A.P.; et al. Estrogen modulates AT 1 receptor gene expression in vitro and in vivo. Circulation 1998, 97, 2197. [Google Scholar] [CrossRef] [PubMed]
  42. Straub, R.H. The complex role of estrogens in inflammation. Endocr. Rev. 2007, 28, 521–574. [Google Scholar] [CrossRef] [PubMed]
  43. Bakir, S.; Mori, T.; Durand, J.; Chen, Y.F.; Thompson, J.A.; Oparil, S. Estrogen-induced vasoprotection is estrogen receptor dependent: Evidence from the balloon-injured rat carotid artery model. Circulation 2000, 101, 2342–2344. [Google Scholar] [CrossRef] [PubMed]
  44. Miller, A.P.; Feng, W.; Xing, D.; Weathington, N.M.; Blalock, J.E.; Chen, Y.F.; Oparil, S. Estrogen modulates inflammatory mediator expression and neutrophil chemotaxis in injured arteries. Circulation 2004, 110, 1664–1669. [Google Scholar] [CrossRef] [PubMed]
  45. Xing, D.; Miller, A.; Novak, L.; Rocha, R.; Chen, Y.F.; Oparil, S. Estradiol and progestins differentially modulate leukocyte infiltration after vascular injury. Circulation 2004, 109, 234–241. [Google Scholar] [CrossRef] [PubMed]
  46. Caulin-Glaser, T.; Watson, C.A.; Pardi, R.; Bender, J.R. Effects of 17β-estradiol on cytokine-induced endothelial cell adhesion molecule expression. J. Clin. Investig. 1996, 98, 36–42. [Google Scholar] [CrossRef] [PubMed]
  47. Alvarez, A.; Hermenegildo, C.; Issekutz, A.C.; Esplugues, J.V.; Sanz, M.J. Estrogens inhibit angiotensin II-induced leukocyte-endothelial cell interactions in vivo via rapid endothelial nitric oxide synthase and cyclooxygenase activation. Circ. Res. 2002, 91, 1142–1150. [Google Scholar] [CrossRef] [PubMed]
  48. Mikkola, T.S.; St Clair, R.W. Estradiol reduces basal and cytokine induced monocyte adhesion to endothelial cells. Maturitas 2002, 41, 313–319. [Google Scholar] [CrossRef]
  49. Abu-Taha, M.; Rius, C.; Hermenegildo, C.; Noguera, I.; Cerda-Nicolas, J.-M.; Issekutz, A.C.; Jose, P.J.; Cortijo, J.; Morcillo, E.J.; Sanz, M.-J. Menopause and Ovariectomy Cause a Low Grade of Systemic Inflammation that May Be Prevented by Chronic Treatment with Low Doses of Estrogen or Losartan. J. Immunol. 2009, 183, 1393. [Google Scholar] [CrossRef] [PubMed]
  50. Mori, T.; Durand, J.; Chen, Y.; Thompson, J.A.; Bakir, S.; Oparil, S. Effects of short-term estrogen treatment on the neointimal response to balloon injury of rat carotid artery. Am. J. Cardiol. 2000, 85, 1276–1279. [Google Scholar] [CrossRef]
  51. Terauchi, M.; Honjo, H.; Mizunuma, H.; Aso, T. Effects of oral estradiol and levonorgestrel on cardiovascular risk markers in postmenopausal women. Arch. Gynecol. Obstet. 2012, 285, 1647–1656. [Google Scholar] [CrossRef] [PubMed]
  52. Kushwaha, R.S.; Born, K.M. Effect of estrogen and progesterone on the hepatic cholesterol 7-α-hydroxylase activity in ovariectomized baboons. Biochim. Biophys. Acta 1991, 1084, 300–302. [Google Scholar] [CrossRef]
  53. Walsh, B.W.; Schiff, I.; Rosner, B.; Greenberg, L.; Ravnikar, V.; Sacks, F.M. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N. Engl. J. Med. 1991, 325, 1196–1204. [Google Scholar] [CrossRef] [PubMed]
  54. McCrohon, J.A.; Nakhla, S.; Jessup, W.; Stanley, K.K.; Celermajer, D.S. Estrogen and progesterone reduce lipid accumulation in human monocyte-derived macrophages: A sex-specific effect. Circulation 1999, 100, 2319–2325. [Google Scholar] [CrossRef] [PubMed]
  55. Wang, H.; Liu, Y.; Zhu, L.; Wang, W.; Wan, Z.; Chen, F.; Wu, Y.; Zhou, J.; Yuan, Z. 17β-estradiol promotes cholesterol efflux from vascular smooth muscle cells through a liver X receptor α-dependent pathway. Int. J. Mol. Med. 2014, 33, 550–558. [Google Scholar] [CrossRef] [PubMed]
  56. Gardner, G.; Banka, C.L.; Roberts, K.A.; Mullick, A.E.; Rutledge, J.C. Modified LDL-mediated increases in endothelial layer permeability are attenuated with 17 β-estradiol. Arterioscler. Thromb. Vasc. Biol. 1999, 19, 854–861. [Google Scholar] [CrossRef] [PubMed]
  57. Florian, M.; Magder, S. Estrogen decreases TNF-α and oxidized LDL induced apoptosis in endothelial cells. Steroids 2008, 73, 47–58. [Google Scholar] [CrossRef] [PubMed]
  58. Walsh, B.A.; Mullick, A.E.; Walzem, R.L.; Rutledge, J.C. 17β-estradiol reduces tumor necrosis factor-α-mediated LDL accumulation in the artery wall. J. Lipid Res. 1999, 40, 387–396. [Google Scholar] [PubMed]
  59. Mooradian, A.D. Antioxidant properties of steroids. J. Steroid Biochem. Mol. Biol. 1993, 45, 509–511. [Google Scholar] [CrossRef]
  60. Strehlow, K.; Rotter, S.; Wassmann, S.; Adam, O.; Grohe, C.; Laufs, K.; Bohm, M.; Nickenig, G. Modulation of antioxidant enzyme expression and function by estrogen. Circ. Res. 2003, 93, 170–177. [Google Scholar] [CrossRef] [PubMed]
  61. Liu, Z.; Gou, Y.; Zhang, H.; Zuo, H.; Zhang, H.; Liu, Z.; Yao, D. Estradiol improves cardiovascular function through up-regulation of SOD2 on vascular wall. Redox Biol. 2014, 3, 88–99. [Google Scholar] [CrossRef] [PubMed]
  62. Wagner, A.H.; Schroeter, M.R.; Hecker, M. 17β-estradiol inhibition of NADPH oxidase expression in human endothelial cells. FASEB J. 2001, 15, 2121–2130. [Google Scholar] [CrossRef] [PubMed]
  63. Vidal-Gomez, X.; Novella, S.; Perez-Monzo, I.; Garabito, M.; Dantas, A.P.; Segarra, G.; Hermenegildo, C.; Medina, P. Decreased bioavailability of nitric oxide in aorta from ovariectomized senescent mice. Role of cyclooxygenase. Exp. Gerontol. 2016, 76, 1–8. [Google Scholar] [CrossRef] [PubMed]
  64. Yan, M.S.; Marsden, P.A. Epigenetics in the Vascular Endothelium: Looking From a Different Perspective in the Epigenomics Era. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 2297–2306. [Google Scholar] [CrossRef] [PubMed]
  65. Abi Khalil, C. The emerging role of epigenetics in cardiovascular disease. Ther. Adv. Chronic Dis. 2014, 5, 178–187. [Google Scholar] [CrossRef] [PubMed]
  66. Voelter-Mahlknecht, S. Epigenetic associations in relation to cardiovascular prevention and therapeutics. Clin. Epigenetics 2016, 8, 4. [Google Scholar] [CrossRef] [PubMed]
  67. Post, W.S.; Goldschmidt-Clermont, P.J.; Wilhide, C.C.; Heldman, A.W.; Sussman, M.S.; Ouyang, P.; Milliken, E.E.; Issa, J.-P.J. Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system. Cardiovasc. Res. 1999, 43, 985–991. [Google Scholar] [CrossRef]
  68. Kim, J.; Kim, J.Y.; Song, K.S.; Lee, Y.H.; Seo, J.S.; Jelinek, J.; Goldschmidt-Clermont, P.J.; Issa, J.-P.J. Epigenetic changes in estrogen receptor β gene in atherosclerotic cardiovascular tissues and in-vitro vascular senescence. Biochim. Biophys. Acta 2007, 1772, 72–80. [Google Scholar] [CrossRef] [PubMed]
  69. Kawagoe, J.; Ohmichi, M.; Tsutsumi, S.; Ohta, T.; Takahashi, K.; Kurachi, H. Mechanism of the Divergent Effects of Estrogen on the Cell Proliferation of Human Umbilical Endothelial Versus Aortic Smooth Muscle Cells. Endocrinology 2007, 148, 6092–6099. [Google Scholar] [CrossRef] [PubMed]
  70. Bendale, D.S.; Karpe, P.A.; Chhabra, R.; Shete, S.P.; Shah, H.; Tikoo, K. 17-β Oestradiol prevents cardiovascular dysfunction in post-menopausal metabolic syndrome by affecting SIRT1/AMPK/H3 acetylation. Br. J. Pharmacol. 2013, 170, 779–795. [Google Scholar] [CrossRef] [PubMed]
  71. Mercer, T.R.; Dinger, M.E.; Mattick, J.S. Long non-coding RNAs: Insights into functions. Nat. Rev. Genet. 2009, 10, 155–159. [Google Scholar] [CrossRef] [PubMed]
  72. Kaikkonen, M.U.; Lam, M.T.; Glass, C.K. Non-coding RNAs as regulators of gene expression and epigenetics. Cardiovasc. Res. 2011, 90, 430–440. [Google Scholar] [CrossRef] [PubMed]
  73. Shi, W.; Hendrix, D.; Levine, M.; Haley, B. A distinct class of small RNAs arises from pre-miRNA-proximal regions in a simple chordate. Nat. Struct. Mol. Biol. 2009, 16, 183–189. [Google Scholar] [CrossRef] [PubMed]
  74. Zhao, J.; Schnitzler, G.R.; Iyer, L.K.; Aronovitz, M.J.; Baur, W.E.; Karas, R.H. MicroRNA-Offset RNA Alters Gene Expression and Cell Proliferation. PLoS ONE 2016, 11, e0156772. [Google Scholar] [CrossRef] [PubMed]
  75. Kim, V.N.; Han, J.; Siomi, M.C. Biogenesis of small RNAs in animals. Nat. Rev. Mol. Cell Biol. 2009, 10, 126–139. [Google Scholar] [CrossRef] [PubMed]
  76. Sobrino, A.; Mata, M.; Laguna-Fernandez, A.; Novella, S.; Oviedo, P.J.; Garcia-Perez, M.A.; Tarin, J.J.; Cano, A.; Hermenegildo, C. Estradiol stimulates vasodilatory and metabolic pathways in cultured human endothelial cells. PLoS ONE 2009, 4, e8242. [Google Scholar] [CrossRef] [PubMed]
  77. Cheng, C.; Fu, X.; Alves, P.; Gerstein, M. mRNA expression profiles show differential regulatory effects of microRNAs between estrogen receptor-positive and estrogen receptor-negative breast cancer. Genome Biol. 2009, 10, R90. [Google Scholar] [CrossRef] [PubMed]
  78. Cizeron-Clairac, G.; Lallemand, F.; Vacher, S.; Lidereau, R.; Bieche, I.; Callens, C. MiR-190b, the highest up-regulated miRNA in ERα-positive compared to ERα-negative breast tumors, a new biomarker in breast cancers? BMC Cancer 2015, 15, 499. [Google Scholar] [CrossRef] [PubMed]
  79. Bhat-Nakshatri, P.; Wang, G.; Collins, N.R.; Thomson, M.J.; Geistlinger, T.R.; Carroll, J.S.; Brown, M.; Hammond, S.; Srour, E.F.; Liu, Y.; et al. Estradiol-regulated microRNAs control estradiol response in breast cancer cells. Nucleic Acids Res. 2009, 37, 4850–4861. [Google Scholar] [CrossRef] [PubMed]
  80. Cochrane, D.R.; Cittelly, D.M.; Howe, E.N.; Spoelstra, N.S.; McKinsey, E.L.; LaPara, K.; Elias, A.; Yee, D.; Richer, J.K. MicroRNAs link estrogen receptor α status and Dicer levels in breast cancer. Horm. Cancer 2010, 1, 306–319. [Google Scholar] [CrossRef] [PubMed]
  81. Paris, O.; Ferraro, L.; Grober, O.M.; Ravo, M.; De Filippo, M.R.; Giurato, G.; Nassa, G.; Tarallo, R.; Cantarella, C.; Rizzo, F.; et al. Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer. Oncogene 2012, 31, 4196–4206. [Google Scholar] [CrossRef] [PubMed]
  82. Nothnick, W.B.; Healy, C.; Hong, X. Steroidal regulation of uterine miRNAs is associated with modulation of the miRNA biogenesis components Exportin-5 and Dicer1. Endocrine 2010, 37, 265–273. [Google Scholar] [CrossRef] [PubMed]
  83. Castellano, L.; Giamas, G.; Jacob, J.; Coombes, R.C.; Lucchesi, W.; Thiruchelvam, P.; Barton, G.; Jiao, L.R.; Wait, R.; Waxman, J.; et al. The estrogen receptor-α-induced microRNA signature regulates itself and its transcriptional response. Proc. Natl. Acad. Sci. USA 2009, 106, 15732–15737. [Google Scholar] [CrossRef] [PubMed]
  84. Klinge, C.M. miRNAs and estrogen action. Trends Endocrinol. Metab. 2012, 23, 223–233. [Google Scholar] [CrossRef] [PubMed]
  85. Al-Nakhle, H.; Burns, P.A.; Cummings, M.; Hanby, A.M.; Hughes, T.A.; Satheesha, S.; Shaaban, A.M.; Smith, L.; Speirs, V. Estrogen receptor {β}1 expression is regulated by miR-92 in breast cancer. Cancer Res. 2010, 70, 4778–4784. [Google Scholar] [CrossRef] [PubMed]
  86. Zhang, H.; Wang, X.; Chen, Z.; Wang, W. MicroRNA-424 suppresses estradiol-induced cell proliferation via targeting GPER in endometrial cancer cells. Cell. Mol. Biol. 2015, 61, 96–101. [Google Scholar] [PubMed]
  87. Yang, W.J.; Yang, D.D.; Na, S.; Sandusky, G.E.; Zhang, Q.; Zhao, G. Dicer is required for embryonic angiogenesis during mouse development. J. Biol. Chem. 2005, 280, 9330–9335. [Google Scholar] [CrossRef] [PubMed]
  88. Suarez, Y.; Fernandez-Hernando, C.; Pober, J.S.; Sessa, W.C. Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells. Circ. Res. 2007, 100, 1164–1173. [Google Scholar] [CrossRef] [PubMed]
  89. Kuehbacher, A.; Urbich, C.; Zeiher, A.M.; Dimmeler, S. Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Circ. Res. 2007, 101, 59–68. [Google Scholar] [CrossRef] [PubMed]
  90. Sharma, S.; Eghbali, M. Influence of sex differences on microRNA gene regulation in disease. Biol. Sex Differ. 2014, 5, 3. [Google Scholar] [CrossRef] [PubMed]
  91. Guo, L.; Zhang, Q.; Ma, X.; Wang, J.; Liang, T. miRNA and mRNA expression analysis reveals potential sex-biased miRNA expression. Sci. Rep. 2017, 7, 39812. [Google Scholar] [CrossRef] [PubMed]
  92. Klinge, C.M. Estrogen action: Receptors, transcripts, cell signaling, and non-coding RNAs in normal physiology and disease. Mol. Cell. Endocrinol. 2015, 418, 191–192. [Google Scholar] [CrossRef] [PubMed]
  93. Chen, J.; Li, K.; Pang, Q.; Yang, C.; Zhang, H.; Wu, F.; Cao, H.; Liu, H.; Wan, Y.; Xia, W.; et al. Identification of suitable reference gene and biomarkers of serum miRNAs for osteoporosis. Sci. Rep. 2016, 6, 36347. [Google Scholar] [CrossRef] [PubMed]
  94. Kangas, R.; Tormakangas, T.; Fey, V.; Pursiheimo, J.; Miinalainen, I.; Alen, M.; Kaprio, J.; Sipila, S.; Saamanen, A.M.; Kovanen, V.; et al. Aging and serum exomiR content in women-effects of estrogenic hormone replacement therapy. Sci. Rep. 2017, 7, 42702. [Google Scholar] [CrossRef] [PubMed]
  95. Evangelista, A.M.; Deschamps, A.M.; Liu, D.; Raghavachari, N.; Murphy, E. miR-222 contributes to sex-dimorphic cardiac eNOS expression via ets-1. Physiol. Genom. 2013, 45, 493–498. [Google Scholar] [CrossRef] [PubMed]
  96. Queirós, A.M.; Eschen, C.; Fliegner, D.; Kararigas, G.; Dworatzek, E.; Westphal, C.; Sanchez Ruderisch, H.; Regitz-Zagrosek, V. Sex- and estrogen-dependent regulation of a miRNA network in the healthy and hypertrophied heart. Int. J. Cardiol. 2013, 169, 331–338. [Google Scholar] [CrossRef] [PubMed]
  97. Petrov, G.; Regitz-Zagrosek, V.; Lehmkuhl, E.; Krabatsch, T.; Dunkel, A.; Dandel, M.; Dworatzek, E.; Mahmoodzadeh, S.; Schubert, C.; Becher, E.; et al. Regression of Myocardial Hypertrophy After Aortic Valve Replacement. Circulation 2010, 122, S23. [Google Scholar] [CrossRef] [PubMed]
  98. Wang, N.; Sun, L.-Y.; Zhang, S.-C.; Wei, R.; Xie, F.; Liu, J.; Yan, Y.; Duan, M.-J.; Sun, L.-L.; Sun, Y.-H.; et al. MicroRNA-23a Participates in Estrogen Deficiency Induced Gap Junction Remodeling of Rats by Targeting GJA1. Int. J. Biol. Sci. 2015, 11, 390–403. [Google Scholar] [CrossRef] [PubMed]
  99. Gowd, B.M.P.; Thompson, P.D. Effect of Female Sex on Cardiac Arrhythmias. Cardiol. Rev. 2012, 20, 297–303. [Google Scholar] [CrossRef] [PubMed]
  100. Siegel, C.; Li, J.; Liu, F.; Benashski, S.E.; McCullough, L.D. miR-23a regulation of X-linked inhibitor of apoptosis (XIAP) contributes to sex differences in the response to cerebral ischemia. Proc. Natl. Acad. Sci. USA 2011, 108, 11662–11667. [Google Scholar] [CrossRef] [PubMed]
  101. Chauhan, A.; Moser, H.; McCullough, L.D. Sex differences in ischaemic stroke: Potential cellular mechanisms. Clin. Sci. 2017, 131, 533. [Google Scholar] [CrossRef] [PubMed]
  102. Wang, L.; Tang, Z.P.; Zhao, W.; Cong, B.H.; Lu, J.Q.; Tang, X.L.; Li, X.H.; Zhu, X.Y.; Ni, X. MiR-22/Sp-1 Links Estrogens With the Up-Regulation of Cystathionine gamma-Lyase in Myocardium, Which Contributes to Estrogenic Cardioprotection Against Oxidative Stress. Endocrinology 2015, 156, 2124–2137. [Google Scholar] [CrossRef] [PubMed]
  103. Schweisgut, J.; Schutt, C.; Wust, S.; Wietelmann, A.; Ghesquiere, B.; Carmeliet, P.; Drose, S.; Korach, K.S.; Braun, T.; Boettger, T. Sex-specific, reciprocal regulation of ERα and miR-22 controls muscle lipid metabolism in male mice. EMBO J. 2017, 36, 1199–1214. [Google Scholar] [CrossRef] [PubMed]
  104. Zhao, J.; Imbrie, G.A.; Baur, W.E.; Iyer, L.K.; Aronovitz, M.; Kershaw, T.B.; Haselmann, G.M.; Lu, Q.; Karas, R.H. Estrogen receptor-mediated regulation of microRNA inhibits proliferation of vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 2013, 33, 257–265. [Google Scholar] [CrossRef] [PubMed]
  105. Deng, L.; Blanco, F.J.; Stevens, H.; Lu, R.; Caudrillier, A.; McBride, M.; McClure, J.D.; Grant, J.; Thomas, M.; Frid, M.; et al. MicroRNA-143 Activation Regulates Smooth Muscle and Endothelial Cell Crosstalk in Pulmonary Arterial Hypertension. Circ. Res. 2015, 117, 870–883. [Google Scholar] [CrossRef] [PubMed]
  106. Vidal-Gomez, X.; Pérez-Cremades, D.; Mompeón, A.; Dantas, A.P.; Novella, S.; Hermenegildo, C. microRNA as crucial regulators of gene expression in estradiol-treated human endothelial cells. Cell. Physiol. Biochem. 2018, in press. [Google Scholar]
  107. Li, P.; Wei, J.; Li, X.; Cheng, Y.; Chen, W.; Cui, Y.; Simoncini, T.; Gu, Z.; Yang, J.; Fu, X. 17β-estradiol enhances vascular endothelial Ets-1/miR-126-3p expression: The possible mechanism for attenuation of atherosclerosis. J. Clin. Endocrinol. Metab. 2016, 102, 594–603. [Google Scholar] [CrossRef] [PubMed]
  108. Fairweather, D. Sex Differences in Inflammation during Atherosclerosis. Clin. Med. Insights Cardiol. 2014, 8 (Suppl. 3), 49–59. [Google Scholar] [CrossRef] [PubMed]
  109. Murphy, A.J.; Guyre, P.M.; Pioli, P.A. Estradiol suppresses NF-κB activation through coordinated regulation of let-7a and miR-125b in primary human macrophages. J. Immunol. 2010, 184, 5029–5037. [Google Scholar] [CrossRef] [PubMed]
  110. Dai, R.; Phillips, R.A.; Zhang, Y.; Khan, D.; Crasta, O.; Ahmed, S.A. Suppression of LPS-induced Interferon-γ and nitric oxide in splenic lymphocytes by select estrogen-regulated microRNAs: A novel mechanism of immune modulation. Blood 2008, 112, 4591–4597. [Google Scholar] [CrossRef] [PubMed]
  111. Olivieri, F.; Ahtiainen, M.; Lazzarini, R.; Pöllänen, E.; Capri, M.; Lorenzi, M.; Fulgenzi, G.; Albertini, M.C.; Salvioli, S.; Alen, M.J.; 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 2014, 13, 850–861. [Google Scholar] [CrossRef] [PubMed]
  112. An, J.H.; Ohn, J.H.; Song, J.A.; Yang, J.-Y.; Park, H.; Choi, H.J.; Kim, S.W.; Kim, S.Y.; Park, W.-Y.; Shin, C.S. Changes of MicroRNA Profile and MicroRNA-mRNA Regulatory Network in Bones of Ovariectomized Mice. J. Bone Miner. Res. 2014, 29, 644–656. [Google Scholar] [CrossRef] [PubMed]
  113. Richelson, L.S.; Wahner, H.W.; Melton, L.J.I.; Riggs, B.L. Relative Contributions of Aging and Estrogen Deficiency to Postmenopausal Bone Loss. N. Engl. J. Med. 1984, 311, 1273–1275. [Google Scholar] [CrossRef] [PubMed]
  114. Kangas, R.; Pollanen, E.; Rippo, M.R.; Lanzarini, C.; Prattichizzo, F.; Niskala, P.; Jylhava, J.; Sipila, S.; Kaprio, J.; Procopio, A.D.; et al. Circulating miR-21, miR-146a and Fas ligand respond to postmenopausal estrogen-based hormone replacement therapy-a study with monozygotic twin pairs. Mech. Ageing Dev. 2014, 143–144, 1–8. [Google Scholar] [CrossRef] [PubMed]
  115. Goedeke, L.; Rotllan, N.; Canfrán-Duque, A.; Aranda, J.F.; Ramírez, C.M.; Araldi, E.; Lin, C.-S.; Anderson, N.N.; Wagschal, A.; de Cabo, R.; et al. Identification of miR-148a as a novel regulator of cholesterol metabolism. Nat. Med. 2015, 21, 1280–1289. [Google Scholar] [CrossRef] [PubMed]
  116. Windler, E.E.; Kovanen, P.T.; Chao, Y.S.; Brown, M.S.; Havel, R.J.; Goldstein, J.L. The estradiol-stimulated lipoprotein receptor of rat liver. A binding site that membrane mediates the uptake of rat lipoproteins containing apoproteins B and E. J. Biol. Chem. 1980, 255, 10464–10471. [Google Scholar] [PubMed]
  117. Goedeke, L.; Rotllan, N.; Ramírez, C.M.; Aranda, J.F.; Canfrán-Duque, A.; Araldi, E.; Fernández-Hernando, A.; Langhi, C.; de Cabo, R.; Baldán, Á.; et al. miR-27b inhibits LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels in mice. Atherosclerosis 2015, 243, 499–509. [Google Scholar] [CrossRef] [PubMed]
  118. Dolz, S.; Górriz, D.; Tembl, J.I.; Sánchez, D.; Fortea, G.; Parkhutik, V.; Lago, A. Circulating MicroRNAs as Novel Biomarkers of Stenosis Progression in Asymptomatic Carotid Stenosis. Stroke 2016, 48, 10–16. [Google Scholar] [CrossRef] [PubMed]
  119. Buratti, L.; Balestrini, S.; Avitabile, E.; Altamura, C.; Vernieri, F.; Viticchi, G.; Falsetti, L.; Provinciali, L.; Silvestrini, M. Sex-associated differences in the modulation of vascular risk in patients with asymptomatic carotid stenosis. J. Cereb. Blood Flow Metab. 2015, 35, 684–688. [Google Scholar] [CrossRef] [PubMed]
  120. Zhang, J.; Li, S.-F.; Chen, H.; Song, J.-X. MiR-106b-5p Inhibits Tumor Necrosis Factor-induced Apoptosis by Targeting Phosphatase and Tensin Homolog Deleted on Chromosome 10 in Vascular Endothelial Cells. Chin. Med. J. 2016, 129, 1406–1412. [Google Scholar] [PubMed]
  121. Noh, E.M.; Lee, Y.R.; Chay, K.O.; Chung, E.Y.; Jung, S.H.; Kim, J.S.; Youn, H.J. Estrogen receptor α induces down-regulation of PTEN through PI3-kinase activation in breast cancer cells. Mol. Med. Rep. 2011, 4, 215–219. [Google Scholar] [PubMed]
  122. Smith, J.A.; Zhang, R.; Varma, A.K.; Das, A.; Ray, S.K.; Banik, N.L. Estrogen partially down-regulates PTEN to prevent apoptosis in VSC4.1 motoneurons following exposure to IFN-γ. Brain Res. 2009, 1301 (Suppl. C), 163–170. [Google Scholar] [CrossRef] [PubMed]
  123. Fish, J.E.; Santoro, M.M.; Morton, S.U.; Yu, S.; Yeh, R.F.; Wythe, J.D.; Ivey, K.N.; Bruneau, B.G.; Stainier, D.Y.; Srivastava, D. miR-126 regulates angiogenic signaling and vascular integrity. Dev. Cell 2008, 15, 272–284. [Google Scholar] [CrossRef] [PubMed]
  124. Wang, S.; Aurora, A.B.; Johnson, B.A.; Qi, X.; McAnally, J.; Hill, J.A.; Richardson, J.A.; Bassel-Duby, R.; Olson, E.N. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev. Cell 2008, 15, 261–271. [Google Scholar] [CrossRef] [PubMed]
  125. Harris, T.A.; Yamakuchi, M.; Ferlito, M.; Mendell, J.T.; Lowenstein, C.J. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc. Natl. Acad. Sci. USA 2008, 105, 1516–1521. [Google Scholar] [CrossRef] [PubMed]
Ijms 19 00473 g001 550
Figure 1. MicroRNA biosynthesis pathway. MicroRNAs (miRNAs) are transcribed by RNA polymerase II (Pol II) activity to generate the primary transcripts (pri-miRNAs). miRNA production is a two-step process involving nuclear cropping and cytosolic dicing processes. First, pri-miRNA cleavage is mediated by a processing complex comprising the RNase III, Drosha, and DiGeorge syndrome critical region 8 (DGCR8), which is also known as the microprocessor complex. This generates a hairpin-shaped pre-miRNA, which is recognized by nuclear exportin 5 and is exported to the cytoplasm where the RNase III, Dicer, cleaves pre-miRNA into 22-nucleotide miRNA duplexes. One strand from the cleavage products remains as a mature miRNA on the Argonaute (AGO) 1–4 proteins, whereas the other strand is degraded. Dicer, TAR RNA-binding protein (TRBP), protein kinase R-activating protein (PACT), and AGO 1–4 proteins mediate the assembly of the RISC (RNA-induced silencing complex). Finally, miRNAs guide translational repression by base-pairing with their target mRNAs, while AGO proteins recruit factors that induce this translational repression.
Figure 1. MicroRNA biosynthesis pathway. MicroRNAs (miRNAs) are transcribed by RNA polymerase II (Pol II) activity to generate the primary transcripts (pri-miRNAs). miRNA production is a two-step process involving nuclear cropping and cytosolic dicing processes. First, pri-miRNA cleavage is mediated by a processing complex comprising the RNase III, Drosha, and DiGeorge syndrome critical region 8 (DGCR8), which is also known as the microprocessor complex. This generates a hairpin-shaped pre-miRNA, which is recognized by nuclear exportin 5 and is exported to the cytoplasm where the RNase III, Dicer, cleaves pre-miRNA into 22-nucleotide miRNA duplexes. One strand from the cleavage products remains as a mature miRNA on the Argonaute (AGO) 1–4 proteins, whereas the other strand is degraded. Dicer, TAR RNA-binding protein (TRBP), protein kinase R-activating protein (PACT), and AGO 1–4 proteins mediate the assembly of the RISC (RNA-induced silencing complex). Finally, miRNAs guide translational repression by base-pairing with their target mRNAs, while AGO proteins recruit factors that induce this translational repression.
Ijms 19 00473 g001
Table
Table 1. Microarray expression data for key miRNA biosynthesis pathway molecules. mRNA expression data were obtained from previously published mRNA microarray data obtained for human umbilical vein endothelial cells (HUVECs) treated with 1 nmol/L estradiol for 24 h. The probe set ID, gene symbol, official full name, p-value, and fold change are shown. These mRNA microarray data are deposited in NCBI’s Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo), accessible through GEO series accession number GSE16683.
Table 1. Microarray expression data for key miRNA biosynthesis pathway molecules. mRNA expression data were obtained from previously published mRNA microarray data obtained for human umbilical vein endothelial cells (HUVECs) treated with 1 nmol/L estradiol for 24 h. The probe set ID, gene symbol, official full name, p-value, and fold change are shown. These mRNA microarray data are deposited in NCBI’s Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo), accessible through GEO series accession number GSE16683.
Probe Set IDSymbolOfficial Full NameFold Changep Value
218269_atDROSHAdrosha, ribonuclease type III−1.1170.586
64474_g_atDGCR8DiGeorge syndrome critical region gene 82.3760.016
223056_s_atXPO5exportin 51.5140.259
213229_atDICER1dicer 1, ribonuclease type III−1.9790.012
225569_atAGO-2argonaute-2−1.2900.002
Table
Table 2. miRNA-dependent estrogen actions. Focusing on the role of estrogen in cardiovascular system and in HRT, estrogen-dependent effect and its associated estrogen-related miRNA are shown.
Table 2. miRNA-dependent estrogen actions. Focusing on the role of estrogen in cardiovascular system and in HRT, estrogen-dependent effect and its associated estrogen-related miRNA are shown.
Estrogen ActionmiRNAReferences
Sex differences in heartmiR-1 miR-106b miR-720 miR-29b miR-144 miR-34b-5p miR-205 miR-222[95]
Sex differences in cardiac fibrosismiR-21 miR-24
miR-27a/b miR-106a/b		[96]
Cardiac gap junction regulationmiR-23a[98]
Regulation of oxidative stress in the myocardiummiR-22[102]
Inhibition of VSMC proliferationmiR-203[104]
VSMC and endothelial cell communication miR-143 miR-145[105]
Endothelial cell proliferationmiR-126-3p[107]
miRNA expression profile in estradiol-treated endothelial cellsmiR-30b-5p miR487a-5p miR-4710
miR-501-3p miR-378h miR-1244		[106]
Regulation of NF-kB pathway in macrophageslet-7a and miR-125b[109]
Regulation of IFNγ released in lymphocytesmiR-146a miR-223[110]
Regulation of Insulin/IGF-1 pathway in skeletal musclemiR-182 and miR-223[111]
Circulating
Inflammation markers		miR-21 miR-146a[105]
Negative regulation of bone mass.miR-127 and miR-136[112]
Serum biomarker in osteoporosismiR-30b-5p[93]
Circulating miRNAmiR-106-5p miR-148a-3p miR-27-3p
miR-126-5p miR-28-3p miR-30a-5p		[94]

Share and Cite

MDPI and ACS Style

Pérez-Cremades, D.; Mompeón, A.; Vidal-Gómez, X.; Hermenegildo, C.; Novella, S. miRNA as a New Regulatory Mechanism of Estrogen Vascular Action. Int. J. Mol. Sci. 2018, 19, 473. https://doi.org/10.3390/ijms19020473

AMA Style

Pérez-Cremades D, Mompeón A, Vidal-Gómez X, Hermenegildo C, Novella S. miRNA as a New Regulatory Mechanism of Estrogen Vascular Action. International Journal of Molecular Sciences. 2018; 19(2):473. https://doi.org/10.3390/ijms19020473

Chicago/Turabian Style

Pérez-Cremades, Daniel, Ana Mompeón, Xavier Vidal-Gómez, Carlos Hermenegildo, and Susana Novella. 2018. "miRNA as a New Regulatory Mechanism of Estrogen Vascular Action" International Journal of Molecular Sciences 19, no. 2: 473. https://doi.org/10.3390/ijms19020473

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop