ReviewMechanisms of Estrogen Effects on the Endothelium: An Overview
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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