The Zebrafish (Danio rerio) Is a Relevant Model for Studying Sex-Specific Effects of 17β-Estradiol in the Adult Heart

Abstract

Cardiovascular diseases are a major cause of morbidity and mortality, and there are significant sex differences therein. However, the underlying mechanisms are poorly understood. The steroid hormone 17β-estradiol (E2) is thought to play a major role in cardiovascular sex differences and to be protective, but this may not hold true for males. We aimed at assessing whether the zebrafish is an appropriate model for the study of E2 effects in the heart. We hypothesized that E2 regulates the cardiac contractility of adult zebrafish in a sex-specific manner. Male and female zebrafish were treated with vehicle (control) or E2 and the cardiac contractility was measured 0, 4, 7 and 14 days after treatment initiation using echocardiography. There was no significant effect on the heart rate by E2. Notably, there was a significant decrease in the ejection fraction of male zebrafish treated with E2 compared with controls. By contrast, there was no major difference in the ejection fraction between the two female groups. The dramatic effect in male zebrafish occurred as early as 4 days post treatment initiation. Although there was no significant difference in stroke volume and cardiac output between the two male groups, these were significantly higher in female zebrafish treated with E2 compared with controls. Gene expression analysis revealed that the levels of estrogen receptors were comparable among all groups. In conclusion, our data demonstrate that the adult zebrafish heart robustly responds to E2 and this occurs in a sex-specific manner. Given the benefits of using zebrafish as a model, new targets may be identified for the development of novel cardiovascular therapies for male and female patients. This would contribute towards the realization of personalized medicine.

Role of Biological Sex in the Cardiovascular-Gut Microbiome Axis

“…For example, the steroid hormone 17βestradiol (E2) and its receptors (ER) are thought to play a major role (107)(108)(109)(110)(111). The E2/ER axis has been shown to have vast effects in the CV system, regulating, for example, contractile function (micro), vascular function, metabolic processes, calcium signaling, gene expression and protein abundance (112)(113)(114)(115)(116)(117)(118)(119)(120)(121)(122)(123)(124)(125)(126), which can be sex-dependent (109,(127)(128)(129)(130)(131)(132). Along this line, among various types of hormones with regulatory effects, sex hormones have a key role in the regulation of the distribution of the gut microbiome.…”

Sex-Related Effects on Cardiac Development and Disease

“…A plethora of studies have reported that the E2/ER axis exerts vast effects on the cardiovascular system [ 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 ] and that these effects can be sex-dependent [ 14 , 118 , 119 , 120 , 121 , 122 ]. In this context, several pre-clinical data support the notion that E2 facilitates endogenous cardiac repair processes in animal models of ischemia/reperfusion (I/R) and myocardial infarction (MI) [ 101 , 123 ].…”

Sex/Gender-Specific Imbalance in CVD: Could Physical Activity Help to Improve Clinical Outcome Targeting CVD Molecular Mechanisms in Women?

“…The role of estrogen receptors is indeed crucial in the atherosclerotic process where, in addition to the classical estrogen receptors (i.e., ERα and estrogen receptor-β (ERβ) shown to mediate opposite effects), other receptors may be involved, suggesting that the balance between the different ERs may be responsible for the different responses and effects [23,78]. Moreover, a very recent study on an adult zebrafish model demonstrated that the heart strongly responded to 17β-estradiol in a sex-specific manner, suggesting that zebrafish could be used as a model to identify novel sex-targeted cardiovascular therapies [79]. Finally, a recent study by Tarhouni and co-workers [80] demonstrated an essential role of 17β-estradiol and ERα in flow-mediated remodeling of resistance arteries, suggesting potential synergic impacts of endothelial shear stress and estrogen signaling in terms of vascular adaptation following exercise and training in vivo.…”