Slow‐pressor angiotensin II hypertension and concomitant dendritic NMDA receptor trafficking in estrogen receptor β–containing neurons of the mouse hypothalamic paraventricular nucleus are sex and age dependent

Abstract

The incidence of hypertension increases after menopause. Similar to humans, “slow-pressor” doses of angiotensin II (AngII) increase blood pressure in young males, but not in young female mice. However, AngII increases blood pressure in aged female mice, paralleling reproductive hormonal changes. These changes could influence receptor trafficking in central cardiovascular circuits and contribute to hypertension. Increased post-synaptic NMDA receptor activity in the hypothalamic paraventricular nucleus (PVN) is crucial for the sympathoexcitation driving AngII hypertension. Estrogen receptors beta (ERβ) are present in PVN neurons. We tested the hypothesis that changes in ovarian hormones with age promote susceptibility to AngII hypertension, and influence NMDA receptor NR1 subunit trafficking in ERβ-containing PVN neurons. Transgenic mice expressing enhanced green fluorescent protein (EGFP) in ERβ-containing cells were implanted with osmotic minipumps delivering AngII (600 ng/kg/min) or saline for 2 weeks. AngII increased blood pressure in 2 month-old males and 18 month-old females, but not in 2 month-old females. By electron microscopy, NR1-silver-intensified immunogold (SIG) was mainly in ERβ-EGFP dendrites. At baseline, NR1-SIG density was greater in 2 month-old females than in 2 month-old males or 18 month-old females. After AngII infusion, NR1-SIG density was decreased in 2 month-old females, but increased in 2 month-old males and 18 month-old females. These findings suggest that, in young female mice, NR1 density is decreased in ERβ-PVN dendrites thus reducing NMDA receptor activity and preventing hypertension. Conversely, in young males and aged females, NR1 density is upregulated in ERβ-PVN dendrites and ultimately leads to the neurohumoral dysfunction driving hypertension.

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

“…As previously described (Marques-Lopes et al, 2014), osmotic minipumps (Alzet, Durect Corporation, Cupertino, CA) were filled with AngII dissolved in saline solution (0.9% NaCl in 0.01% bovine serum albumin; BSA) or the saline solution alone (Sal). To determine the appropriate amount of AngII (600 ng/kg/min) mice were weighed prior to pump preparation.…”

“…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).…”

“…Activity-dependent changes in the subcellular localization of GluN1 are a critical component of neural plasticity in a variety of brain regions (Beckerman et al, 2013; Petralia, 2012). Several studies in male mice demonstrate that increased blood pressure is associated with alteration of the subcellular localization of GluN1 in brain areas involved in sympathoexcitatory outflow, including hypothalamic paraventricular nucleus (PVN) neurons (Coleman et al, 2010; Glass et al, 2015; Marques-Lopes et al, 2014; Wang et al, 2013). Little is known, however, about the relationship between hypertension and GluN1 trafficking in the RVLM.…”

“…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). However, the effect of slow-pressor AngII administration on the subcellular distribution GluN1 has not yet been explored in CRF 1 neurons in either the RVLM or PVN.…”