Review
The relevance of estrogen/estrogen receptor system on the gender difference in cardiovascular risk

https://doi.org/10.1016/j.ijcard.2015.03.145Get rights and content

Highlights

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    Thrombosis is at the basis of major cardiovascular disorders.

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    There is a gender disparity in thrombogenesis.

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    Estrogen/estrogen receptors (ERs) influence platelet functions and thrombogenicity.

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    ERβ appears as the predominant form of ER in platelets.

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    Non-nuclear estrogen receptor can trigger prompt functional response in platelets.

Abstract

It has been reported that the incidence of thrombotic events can display a gender disparity. In particular, a lower thrombotic risk has been described in female gender. The mechanisms underlying this disparity are still poorly understood. Of great interest is the hypothesis that hormones, estrogen in particular, could play a key role. In fact, the possibility that some hormonal factors could protect women from thrombotic events appears well documented in literature. For instance, several studies aimed at the analysis of the impact of estrogen and estrogen receptors in thrombogenesis claim for the implication of these hormones either in megakaryocyte differentiation or, more intriguingly, directly affecting platelet integrity and function. In consideration of the absence of the nucleus, platelet susceptibility appears quite striking and probably due to the non-nuclear estrogen receptor function. In this review we briefly summarize our knowledge as concerns the role of estrogen and estrogen receptors in determining megakaryocyte/platelet functions and thrombogenicity.

Introduction

Thrombosis is the commonest cause of death in developed countries. It is the basis of three major cardiovascular disorders: ischemic heart disease (acute coronary syndrome), stroke (arterial cerebral thrombosis) and venous thromboembolism (VTE). Depending on the various pathological conditions a different incidence of thrombotic events between men and women was found. For instance, stroke incidence appears as lower in females than in males until advanced ages, after which the rates rise dramatically in both sexes [1]. Similarly, the recurrent venous thrombosis appears as less frequent in females and, also for the first event, the male/female ratio is 2:1 [2]. These data seem to suggest that some hormonal factors, estrogen in particular, could protect women from thrombotic events. Several insights derive in fact from a number of studies carried out either in animals or in humans. For example, studies carried out in animal models have demonstrated that ovariectomy increases infarct size and that estradiol supplementation reduces injury [3]. In humans, a good example is that represented by the use of oral contraceptives and postmenopausal hormonal therapies, which contain various estrogens: it has been found that these treatments are associated with a weaker risk of both arterial and venous thrombosis [4]. On these bases, it was hypothesized that hormonal (i.e., estrogenic) factors could play a pivotal role in regulating thrombotic events, also influencing the ensuing cardiovascular diseases. Herein, we discuss literature data dealing with this issue: the role of estrogen and estrogen receptors in determining megakaryocyte/platelet integrity and function and in the control of thrombogenicity.

Section snippets

Hormones and thrombosis

The crucial role of hormones in thrombosis and hemostasis in men and women has been analyzed in several works [2], [5]. These works underscore that, although obviously occurring in both sexes, i) the intrinsic risk of VTE is two-fold higher in men than in women; ii) hormonal contraceptives increase the risk of VTE in women and that iii) this risk varies per type, dose, and hormone administration route. On this basis, avoidance of some hormonal contraceptives (as well as thrombosis prophylaxis

Sex differences in platelet function

Platelets can be activated by circulating factors in the blood or by the sub-endothelial collagen during endothelial injury. The interaction between exposed atherosclerotic plaque components, platelet receptors and coagulation factors eventually leads to platelet activation, aggregation and the subsequent formation of a superimposed thrombus (i.e. atherothrombosis), which may compromise the arterial lumen leading to the presentation of acute ischaemic syndromes [19]. Hormones can influence

Hormones and coagulation

Hormone levels can affect the levels of clotting factors and favor an acquired resistance to the actions of activated protein C, leading to an increased risk of VTE [29]. Decreased levels of von Willebrand factor (VWF), fibrinogen, and activated factor VII have been measured during the menstrual cycle [29]. Conversely, pregnancy is a procoagulant state with progressive increase in levels of factors VII, VIII, X, and XII, fibrinogen, and VWF, as well as increased resistance to activated protein

On the estrogen receptors

The effects of estrogen are mediated in part through the activation of two estrogen receptors: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). These receptors function as transcription factors regulating the expression of target genes and can be localized in the nucleus, in the plasma membrane or in the mitochondria. Probably, nuclear and non-nuclear estrogen receptors are not separate units, but rather the components of a complex mechanism in which they cooperate with each

Implication of estrogen/ER interactions in megakaryocytopoiesis

Within the bone marrow compartment stem cells differentiate along mesenchymal and hematopoietic lineages regulated by local and systemic factors. Progenitor cells, called megakaryocytes (MKs), produce numerous colony-forming units (CFU-MK) that differentiate and undergo endomitosis with the generation of large cells with lobulated nuclei. During the final stages of maturation, fragmentation of MK cytoplasm leads to the formation of platelets and their release into the circulation [61]. Recent

mERs

Estrogen may modify platelet function through their interaction with ERs. Moro and collaborators showed that E2 (100 nM) determined calcium entry and platelet aggregation in a synergistic way with thrombin (a physiological agonist of platelet aggregation) [75]. In particular, 17β-estradiol caused the rapid phosphorylation of the tyrosine kinases Src and Pyk2 and the formation of a signaling complex, which includes Src, Pyk2, and the phosphatidylinositol 3-kinase. These events were dependent on

MicroRNAs (miRNAs) and hormones

miRNAs are endogenously expressed, small RNAs (sized about 22 nucleotides) representing the most abundant class of regulators of gene expression. MicroRNAs have the ability to target multiple messenger RNAs (mRNAs) with the consequent inhibition of mRNA translation or degradation. Their dysregulated expression profiles associate with several human diseases, including hemostasis and thrombosis [87]. In consequence, microRNAs have been shown to be useful as diagnostic and prognostic indicators of

Conclusions

All in all, literature data underscore the importance of estrogen in regulating MK function and platelet production. More interestingly, the emerging picture underscores a clear role of estrogens and ERs as key regulators of platelet physiology and pathology. In particular, in this peculiar cell type, ER-associated signaling could be referred as to both mER and mtER and could be related to rapid signals leading to platelet function/dysfunction. The study of these receptors and their signaling

Conflict of interest

The authors report no relationships that could be construed as a conflict of interest.

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