Female protection from slow‐pressor effects of angiotensin II involves prevention of ROS production independent of NMDA receptor trafficking in hypothalamic neurons expressing angiotensin 1A receptors

Abstract

Renin-angiotensin system over-activity, up-regulation of post-synaptic NMDA receptor function, and increased reactive oxygen species (ROS) production in the hypothalamic paraventricular nucleus (PVN) are hallmarks of angiotensin II (AngII)-induced hypertension, which is far more common in young males than in young females. We hypothesize that the sex differences in hypertension are related to differential AngII-induced changes in post-synaptic trafficking of the essential NMDA receptor GluN1 subunit and ROS production in PVN cells expressing angiotensin type 1a receptor (AT1aR). We tested this hypothesis using slow-pressor (14 day) infusion of AngII (600ng/kg/min) in mice, which elicits hypertension in males but not in young females. Two month-old male and female transgenic mice expressing enhanced green fluorescent protein (EGFP) in AT1aR-containing cells were used. In males, but not females, AngII increased blood pressure and ROS production in AT1aR-EGFP PVN cells at baseline and following NMDA treatment. Electron microscopy showed that AngII increased cytoplasmic and total GluN1-silver-intensified immunogold (SIG) densities, and induced a trend towards an increase in near plasmalemmal GluN1-SIG density in AT1aR-EGFP dendrites of males and females. Moreover, AngII decreased dendritic area and diameter in males, but increased dendritic area of small (<1μm) dendrites and decreased diameter of large (>1μm) dendrites in females. Fluorescence microscopy revealed that AT1aR and estrogen receptor β do not co-localize suggesting that, if estrogen is involved, its effect is indirect. The data suggest that the sexual dimorphism in AngII-induced hypertension is associated with sex differences in ROS production in AT1aR-containing PVN cells, but not with post-synaptic NMDA receptor trafficking.

Sex differences in NMDA GluN1 plasticity in rostral ventrolateral medulla neurons containing corticotropin-releasing factor type 1 receptor following slow-pressor angiotensin II hypertension

“…In young male mice, slow-pressor AngII administration results in a slow-onset increase in arterial pressure that develops over several days (Kawada et al, 2002; Zimmerman et al, 2004; Reckelhoff and Romero, 2003). However, young aged-matched female mice do not develop hypertension in response to slow pressor AngII (Marques-Lopes et al, 2015; Marques-Lopes et al, 2014; Xue et al, 2007a). Notably, the subcellular distribution and pattern of GluN1 in distinct populations of PVN dendrites also differs in young male and female mice following slow-pressor AngII administration (Marques-Lopes et al, 2015; Marques-Lopes et al, 2014).…”

“…However, young aged-matched female mice do not develop hypertension in response to slow pressor AngII (Marques-Lopes et al, 2015; Marques-Lopes et al, 2014; Xue et al, 2007a). Notably, the subcellular distribution and pattern of GluN1 in distinct populations of PVN dendrites also differs in young male and female mice following slow-pressor AngII administration (Marques-Lopes et al, 2015; Marques-Lopes et al, 2014). In particular, GluN1 is increased in estrogen receptor (ER) β-containing dendrites in hypertensive males, but decreased in non-hypertensive females (Marques-Lopes et al, 2014).…”

SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington’s disease

“…The data analysis procedure is similar as previously described (92). The images were collected at a magnification of 18,500.…”

Sex, the brain and hypertension: brain oestrogen receptors and high blood pressure risk factors

“…Both ROS and nitric oxide (NO) mechanisms have been implicated [17,62,63]. In recent studies using male and female mice in which the AT1 receptor was co-localized with green fluorescent protein in the PVN [63], the effects of AngII infusion on BP and ROS production in the PVN's AT1-positive cells was determined. As has been shown previously [37], AngII infusion resulted in a significant increase in BP in the males but not in the intact females.…”

“…Are these differences in ER expression in the brain also seen in humans? A common cellular mechanism, regardless of the site of the brain region expression, includes inhibition of ROS formation and enhancement of nNOS expression [63,64]. How we might exploit this understanding of selective expression of ERs in these key brain regions involved in hypertension, to develop ER-selective drugs to treat hypertension, needs further study.…”