Mechanisms underlying the influence of oestrogen on cardiovascular physiology in women

Women show a lower incidence of cardiovascular diseases than aged-matched men, but this benefit disappears after menopause. Oestrogen-mediated vascular actions are mainly attributed to oestradiol and exerted by oestrogen receptors (ERα, ERβ, and GPER), through rapid and/or genomic mechanisms, but these effects depend on ageing and inflammation. A cardiovascular approach in women's health has arisen due to controversy regarding oestrogens' beneficial impact as reported in experimental and observational studies and large randomized trials. These can be explained, in part, by two mutually non-exclusive hypotheses. On the one hand, the timing hypothesis, which states that oestrogen-mediated benefits occur before the detrimental effects of ageing are established in the vasculature; on the other hand, ageing and/or hormonal-associated changes in ER expression that could lead to a deleterious imbalance in favour of ERβ over ERα, generally associated with higher inflammation and endothelial dysfunction. In experimental studies, oestradiol acting on ERα promotes the release of vasoactive compounds such as nitric oxide (NO) and prostacyclin, and shifts the angiotensin axis towards angiotensin 1-7 production. Mechanisms underlying oestradiol vascular function also include anti-inflammatory and epigenetic modifications. 17β-oestradiol changes the transcriptomic profile of endothelial cells, and the involvement of miRNA in the regulatory pathways of vascular function reinforces assumptions regarding the vascular actions of oestrogen. Thus, the present symposium review aims to postulate the role of ERα in oestrogen modulation of endothelial-derived mediators and vascular physiology, as well as its relationship with miRNA and inflammation, and elucidate how physiological changes in postmenopausal women counteract the observed effects

Effects of Estrogen on vascular inflammation: a matter of timing.

Objective: Our study aims to determine the role of time of menopause on vascular inflammation biomarkers and how it affects their modulation by estrogen and raloxifene in postmenopausal women. Methods and results: Uterine arteries from 68 postmenopausal women were divided into 3 segments and cultured for 24 hours in tissue culture media containing 17β-estradiol (100 nmol/L), raloxifene (100 nmol/L), or vehicle. Assessment of arterial concentration of 13 inflammatory biomarkers was performed by multiplex immunobead-based assay. Aging per se has a positive correlation with the generation of several proinflammatory markers. Although short-term estradiol exposure correlates with lower expression of tumor necrosis factor-α, vascular endothelial growth factor, and interleukin-1β in all age groups, for most biomarkers aging was associated with a switch from a beneficial anti-inflammatory action by estrogen, at earlier stages of menopause, to a proinflammatory profile after 5 years past its onset. Raloxifene has no significant effect on the expression of all proinflammatory markers. Western blot analysis of estrogen receptor expression (estrogen receptor-α and estrogen receptor-β) showed that estrogen receptor-β increases with aging, and this increase has a positive correlation with the generation of several proinflammatory markers. Conclusions: Aging alters estrogen-mediated effects on the modulation of inflammatory biomarkers in women. How aging affects estrogen responses on vascular inflammation is not clear, but our data show a positive association between increased estrogen receptor-β expression with aging and proinflammatory effects by estrogen

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

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

miRNA as New Regulatory Mechanism of Estrogen Vascular Action

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

With mouse age comes wisdom : a review and suggestions of relevant mouse models for age-related conditions

Ageing is a complex multifactorial process that results in many changes in physiological changes processes that ultimately increase susceptibility to a wide range of diseases. As such an ageing population is resulting in a pressing need for more and improved treatments across an assortment of diseases. Such treatments can come from a better understanding of the pathogenic pathways which, in turn, can be derived from models of disease. Therefore the more closely the model resembles the disease situation the more likely relevant the data will be that is generated from them. Here we review the state of knowledge of mouse models of a range of diseases and aspects of an ageing physiology that are all germane to ageing. We also give recommendations on the most common mouse models on their relevance to the clinical situations occurring in aged patients and look forward as to how research in ageing models can be carried out. As we continue to elucidate the pathophysiology of disease, often through mouse models, we also learn what is needed to refine these models. Such factors can include better models, reflecting the ageing patient population, or a better phenotypic understanding of existing models

MicroRNA as crucial regulators of gene expression in estradiol-treated human endothelial cells.

Background/Aims: Estrogen signalling plays an important role in vascular biology as it modulates vasoactive and metabolic pathways in endothelial cells. Growing evidence has also established microRNA (miRNA) as key regulators of endothelial function. Nonetheless, the role of estrogen regulation on miRNA profile in endothelial cells is poorly understood. In this study, we aimed to determine how estrogen modulates miRNA profile in human endothelial cells and to explore the role of the different estrogen receptors (ERα, ERβ and GPER) in the regulation of miRNA expression by estrogen. Methods: We used miRNA microarrays to determine global miRNA expression in human umbilical vein endothelial cells (HUVEC) exposed to a physiological concentration of estradiol (E2; 1 nmol/L) for 24 hours. miRNA-gene interactions were computationally predicted using Ingenuity Pathway Analysis and changes in miRNA levels were validated by qRT-PCR. Role of ER in the E2-induced miRNA was additionally confirmed by using specific ER agonists and antagonists. Results: miRNA array revealed that expression of 114 miRNA were significantly modified after E2 exposition. Further biological pathway analysis revealed cell death and survival, lipid metabolism, reproductive system function, as the top functions regulated by E2. We validated changes in the most significantly increased (miR-30b-5p, miR-487a-5p, miR-4710, miR-501-3p) and decreased (miR-378h and miR-1244) miRNA and the role of ER in these E2-induced miRNA was determined. Results showed that both classical, ERα and ERβ, and membrane-bound ER, GPER, differentially regulated specific miRNA. In silico analysis of validated miRNA promoters identified specific ER binding sites. Conclusion: Our findings identify differentially expressed miRNA pathways linked to E2 in human endothelial cells through ER, and provide new insights by which estrogen can modulate endothelial function

Los cambios en las experiencias participativas en el tránsito de la infancia a la adolescencia: Las voces de chicos y chicas de Barcelona, Buenos Aires y Ciudad de México

A lo largo de las distintas etapas del ciclode vida las instituciones cumplen un rol central en la producción social deaquello que se entiende por infancia, adolescencia y juventud. La escuelasecundaria históricamente adquirió un sentido como instancia de transición, entanto un puente entre una etapa y otra de la vida. Fue la imagen de latransición hacia el trabajo, del paso a la vida adulta, el lugar de aprendizajede los saberes socialmente productivos para el acceso a los estudiossuperiores. Esta matriz tenía un signo excluyente, en tanto seleccionaba demanera explícita o implícita a través de un conjunto de prácticasinstitucionalizadas que establecían desigualdades entre quienes se adaptaban ala temporalidad, modos de comportamiento y formas de transmitir el conocimientolegitimadas y quienes desarrollaban otro tipo de trayectorias. En las últimas décadas, persisten algunas de estas dificultadesasí como de los sentidos otorgados socialmente al nivel secundario, pero secombina con expresiones de nuevo signo, a partir de la extensión de los años deescolarización considerados obligatorios y la incorporación en las leyeseducativas de la obligatoriedad del nivel. En este capítulo se presenta una reflexión sobre loscambios en las experiencias de participación que identifican los chicos ychicas en la transición de la infancia a la adolescencia. Las aportaciones quese hacen vienen del análisis de las voces de 13 grupos de discusión con jóvenesentre 15 y 17 años de las ciudades de Barcelona (6), Buenos Aires (4) y Ciudadde México (3). El capítulo está organizado en tres apartados. En el primero se centrael marco de referencia desde donde analizar la representación social de lainfancia, su transición a la adolescencia y la escuela secundaria comoinstancia de tensión entre la temporalidad escolar y los ritmos juveniles. Enel segundo, para cada una de las ciudades se interpretan las aportaciones delos estudiantes en los grupos de discusión alrededor de su visión sobre loscambios en las experiencias de participación en el nivel secundario. Y untercer apartado, donde se identifican algunas similitudes y diferencias entrelas tres ciudades analizadas. [1] Aproximadamente la mitadde los países de la región latinoamericana consideran obligatorio los dosciclos del nivel secundario (básico o inferior) y el superior u orientado deacuerdo con la denominación. En Argentina y México es obligatorio el ciclocompleto, en el primer país desde la sanción de la Ley Nacional de Educación26.206/2006 mientras que en el segundo la más reciente promulgación en elModelo Educativo del 2016. Por su parte en la mayoría de los países de la UniónEuropea, la enseñanza obligatoria es hasta los 16, incluso hasta los 18 como esel caso de Bélgica. En España en concreto, la Educación Secundaria comprende laEducación Secundaria Obligatoria (12 a 16 años), el Bachillerato (16-18 años) yla Formación Profesional (de grado medio y grado superior).Fil: Novella, Susana. Universidad de Barcelona; EspañaFil: Nuñez, Pedro Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto de Investigaciones Sociales de América Latina. - Facultad Latinoamericana de Ciencias Sociales. Instituto de Investigaciones Sociales de América Latina; ArgentinaFil: García Reyes, Jesús. Universidad Autónoma del Estado de México; Méxic

Regulatory network analysis in estradiol-treated human endothelial cells.

Background/Aims: Estrogen has been reported to have beneficial effects on vascular biology through direct actions on endothelium. Together with transcription factors, miRNAs are the major drivers of gene expression and signaling networks. The objective of this study was to identify a com-prehensive regulatory network (miRNA-transcription factor-downstream genes) that controls the transcriptomic changes observed in endothelial cells exposed to estradiol. Methods: miR-NA/mRNA interactions were assembled using our previous microarray data of human umbilical vein endothelial cells (HUVEC) treated with 17ß- Estradiol (E2) (1 nmol/lL, 24 h). miRNA--mRNA pairings and their associated canonical pathways were determined using Ingenuity Pathway Analysis software. Transcription factors were identified among the miR-NA-regulated genes. Transcription factor downstream target genes were predicted by consensus transcription factor binding sites in the promoter region of E2-regulated genes by using JASPAR and TRANSFAC tools in Enrichr software. Results: miRNA--target pairings were filtered by using differentially expressed miRNAs and mRNAs characterized by a regulatory relationship accord-ing to miRNA target prediction databases. The analysis identified 588 miRNA--target interactions between 102 miRNAs and 588 targets. Specifically, 63 up-regregulated miRNAs interacted with 295 down-regregulated targets, while 39 down-regregulated miRNAs were paired with 293 up-regregulated mRNA targets. Functional characterization of miRNA/mRNA association analy-sis highlighted hypoxia signallignaling, integrin, ephrin receptor signaling, and regulation of actin-based motility by Rho among the canonical pathways regulated by E2 in HUVEC. Tran-scription factors and downstream genes analysis revealed a total of eight networks, including those mediated by JUN and REPIN1, which are associated with cadherin binding and cell adhe-sion molecule binding pathways. Conclusion: This study identifies regulatory networks obtained by integrative microarray analysis and provides additional insights into the way estradiol could regulate endothelial function in human endothelial cells