Norepinephrine modulation of heat dissipation in female rats lacking estrogen.

Postmenopausal hot flushes are caused by lack of estradiol (E2) but their neuroendocrine basis is still poorly understood. Here, we investigated the interrelationship between norepinephrine and hypothalamic neurons, with emphasis on kisspeptin neurons in the arcuate nucleus (ARC), as a regulatory pathway in the vasomotor effects of E2. Ovariectomized (OVX) rats displayed increased tail skin temperature (TST), and this increase was prevented in OVX rats treated with E2 (OVX + E2). Expression of Fos in the hypothalamus and the number of ARC kisspeptin neurons coexpressing Fos were increased in OVX rats. Likewise, brainstem norepinephrine neurons of OVX rats displayed higher Fos immunoreactivity associated with the increase in TST. In the ARC, the density of dopamine-ß-hydroxylase (DBH)-immunoreactive (ir) fibers was not altered by E2 but, importantly, DBH-ir terminals were found in close apposition to kisspeptin cells, revealing norepinephrine inputs to ARC kisspeptin neurons. Intracerebroventricular injection of the α2-adrenergic agonist clonidine (CLO) was used to reduce central norepinephrine release, confirmed by the decreased 3-methoxy-4-hydroxyphenylglycol/norepinephrine ratio in the preoptic area and ARC. Accordingly, CLO treatment in OVX rats reduced ARC Kiss1 mRNA levels and TST to the values of OVX + E2 rats. Conversely, CLO stimulated Kiss1 expression in the anteroventral periventricular nucleus (AVPV) and increased luteinizing hormone secretion. These findings provide evidence that augmented heat dissipation in OVX rats involves the increase in central norepinephrine that modulates hypothalamic areas related to thermoregulation, including ARC kisspeptin neurons. This neuronal network is suppressed by E2 and its imbalance may be implicated in the vasomotor symptoms of postmenopausal hot flushes.

17-ß-Estradiol increases macrophage activity through activation of the G-protein-coupled estrogen receptor and improves the response of female mice to Cryptococcus gattii.

Cryptococcus gattii (Cg) is one of the agents of cryptococcosis, a severe systemic mycosis with a higher prevalence in men than women, but the influence of the female sex hormone, 17-ß-estradiol (E2), on cryptococcosis remains unclear. Our study shows that female mice presented delayed mortality, increased neutrophil recruitment in bronchoalveolar lavage fluid, and reduced fungal load after 24 hr of infection compared to male and ovariectomised female mice (OVX). E2 replacement restored OVX female survival. Female macrophages have more efficient fungicidal activity, which was increased by E2 and reversed by the antagonist of G-protein-coupled oestrogen receptor (GPER), which negatively modulates PI3K activation. Furthermore, E2 induces a reduction in Cg cell diameter, cell charge, and antioxidant peroxidase activity. In conclusion, female mice present improved control of Cg infection, and GPER is important for E2 modulation of the female response.

Age-related changes in vascular responses to angiotensin-(1-7) in female mice.

The vasodilatory effect of angiotensin-(1-7) seems to vary between sexes, and estradiol (E2) can modulate the magnitude of the Ang-(1-7) vasodilatory response in female rats. However, there are few studies addressing the influence of sex on the age-related vasodilatory effect of Ang-(1-7). Here, we evaluated the vasodilatory response to Ang-(1-7) on vascular ageing. Ang-(1-7) dose-response curves were determined in mice aortic rings from males (old and young) and females (E2 treated/non-treated old and young) mounted in an isolated organ chamber. Abdominal aortic rings were used for protein expression analysis and determination of reactive oxygen species (ROS) and nitric oxide (NO) production. Our results showed that the Ang-(1-7) vasodilatory effect was absent in aorta from old females, contrasting with a full response in vessels from young females. The Ang-(1-7) vasodilatory effect was restored by E2 replacement in old females. A robust increase in Mas receptor, SOD2, NRF-2 and NOX2 expression was observed in aorta from old females, which was normalized by E2. This effect of E2 was also associated with lower production of ROS and normal levels of NO. In conclusion, our data demonstrated that pathways involved in the Ang-(1-7) vasodilatory response in female mice is affected by hormonal changes in ageing and rescued by E2.