Review
Mechanisms of Estrogen Effects on the Endothelium: An Overview

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Abstract

In this review, we aim to provide an overview of the recent advances in understanding estrogen effects on the vascular endothelium. Epidemiological studies suggest the female sex hormone estrogen mediates the relative protection of premenopausal women against cardiovascular disease, compared with age-matched men. However, results from clinical trials of exogenous estrogen supplementation in postmenopausal women have been disappointing, generating much controversy about the role of estrogen and demonstrating the need for further research in this field. Here we have discussed the roles of different estrogen receptors (ERs) such as ERα, ERβ, and G-protein coupled receptor 30; the complex genomic and nongenomic signalling pathways downstream to ER activation and the factors such as age, menopause, pregnancy, and diabetes that might alter estrogen responses. The common themes of this discussion are the complexity and diversity of endothelial estrogen responses and their modulation by 1 or more coexisting factors. Finally, we summarize the emerging therapeutic options including improved targeting of individual ERs and signalling pathways that might maximize the therapeutic potential of estrogenic compounds while minimizing their harmful side effects.

Résumé

Dans cette revue, notre voulons donner un aperçu des récents progrès en matière de compréhension des effets de l'œstrogène sur l'endothélium vasculaire. Les études épidémiologiques montrent que l'œstrogène, une hormone sexuelle femelle, intervient dans la protection relative des femmes préménopausées contre la maladie cardiovasculaire comparativement aux hommes appariés selon l'âge. Cependant, les résultats des essais cliniques sur la supplémentation en œstrogènes exogènes chez les femmes postménopausées se sont avérés décevants, suscitant une importante controverse sur le rôle de l'œstrogène et démontrant la nécessité de réaliser d'autres recherches dans ce domaine. Ici, nous avons discuté des rôles des différents récepteurs des œstrogènes (ER : estrogen receptor) comme le ERα, le ERβ et le récepteur 30 couplé aux protéines G; les voies de signalisation génomique et non génomique complexe en aval de l'activation des ER et les facteurs comme l'âge, la ménopause, la grossesse et le diabète qui pourraient modifier les réponses aux œstrogènes. Les thèmes communs de cette discussion sont la complexité et la diversité des réponses de l'endothélium aux œstrogènes et leur modulation par 1 facteur coexistant ou plus. Finalement, nous résumons les options thérapeutiques émergentes incluant l'amélioration du ciblage individuel des RO et des voies de signalisation qui pourraient maximiser le potentiel thérapeutique des composantes œstrogéniques tout en minimisant leurs effets secondaires dangereux.

Section snippets

ERs in the Endothelium

The effects of estrogen, especially E2, the common form in the body, are mediated through its specific receptors, which can exert distinct responses through genomic, nongenomic, and combined pathways depending on the specific subtype and subcellular distribution.

Estrogen Signalling Pathways

On binding and activating 1 or more of its 3 known receptors, estrogen activates a range of signalling pathways in different tissues, an overview of which is given later in text.

Vasoactive Targets of Estrogen

Under physiological conditions, the major vascular role for estrogen is mediating vasorelaxation. Endothelial targets of estrogen include the NO pathway involving modulation of eNOS through genomic and nongenomic mechanisms. In addition, estrogen regulates other vasoactive mediators and factors mediating growth/survival/apoptosis, the actin cytoskeleton, and ion channels.

Factors Affecting Endothelial Estrogen Responses

Although estrogen acts through a number of different receptor and signalling pathways, its biological outcomes are also affected by factors such as age, pregnancy, and coexisting pathologies.

Potential Therapeutic Approaches

Considering the complexities of endothelial estrogen signalling, it is clear that exogenous addition of estradiol might be an overly simplistic measure to harness the beneficial estrogenic effects. A number of novel approaches are being taken to maximize the protective estrogen actions on the vascular system, a brief overview of which is given here.

Conclusions

Endothelial estrogen signalling is a complex and evolving topic. Various studies indicate that estrogen acts through multiple receptors, activates different signalling cascades, and its biological effects are influenced by coexisting physiological (eg, age, menopause, pregnancy) and pathological (eg, diabetes) conditions (summarized in Fig. 1). Future therapies would likely focus on the timing of therapy, treatment of associated conditions, and the selective targeting of individual receptors

Funding Sources

The Davidge laboratory is funded by grants from Canadian Institutes of Health Research (CIHR) and the Heart and Stroke Foundation of Canada. S. Davidge is an Alberta Innovates- Health Solutions/Alberta Heritage Foundation for Medical Research (AIHS/AHFMR) Scientist and a Canada Research Chair in Women's Cardiovascular Health.

Disclosures

The authors have no conflicts of interest to disclose.

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