Alterations in the subcellular distribution of NADPH oxidase p47^phox in hypothalamic paraventricular neurons following slow‐pressor angiotensin II hypertension in female mice with accelerated ovarian failure

Abstract

At younger ages, women have a lower risk for hypertension than men, but this sexual dimorphism declines with the onset of menopause. These differences are paralleled in rodents following “slow-pressor” angiotensin II (AngII) administration: young male and aged female mice, but not young females, develop hypertension. There is also an established sexual dimorphism both in the cardiovascular response to the neurohypophyseal hormone arginine vasopressin (AVP) and in the expression of oxidative stress. We examined the relationship between AngII-mediated hypertension and the cellular distribution of the superoxide generating NADPH oxidase (NOX) in AVP-expressing hypothalamic paraventricular nucleus (PVN) neurons in “menopausal” female mice. Dual labeling immunoelectron microscopy was used to determine if the subcellular distribution of the organizer/adapter NOX p47phox subunit is altered in PVN dendrites following AngII administered (14 days) during the “postmenopausal” stage of accelerated ovarian failure (AOF) in young female mice treated with 4-vinylcyclohexene diepoxide. Slow-pressor AngII elevated blood pressure in AOF females and induced a significant a significant increase in near plasmalemmal p47phox and a decrease in cytoplasmic p47phox in PVN AVP dendrites. These changes are opposite to those observed in AngII-induced hypertensive male mice (Coleman et al., J. Neuroscience 33: 4308-16, 2013), and may be ascribed in part to baseline differences between young females and males in the near plasmalemmal p47phox on AVP dendrites seen in the present study. These findings highlight fundamental differences in the neural substrates of oxidative stress in the PVN associated with AngII hypertension in postmenopausal females compared with males.

Understanding the broad influence of sex hormones and sex differences in the brain

“…Like males, slow pressor AngII elevates blood pressure in post-AOF females. However, opposite to males, slow pressor AngII decreases plasmalemmal p47 phox SIG in non-AVP dendrites and increases near plasmalemmal p47 phox SIG in AVP-containing dendrites in post-AOF females (Van Kempen et al 2015b). These findings provide evidence for fundamental sex differences in the hypothalamic changes underlying the neurohumoral regulation of blood pressure (Fig.…”

“…In males, slow-pressor AngII hypertension results in a repartitioning of p47 phox to the plasmalemma of PVN neurons that do not express arginine vasopressin (AVP), along with a concomitant increase in ROS production (Coleman et al 2013). At baseline, young females have a greater density of p47 phox SIG near the plasma membrane of AVP-containing dendrites than males m(Van Kempen et al 2015b). Compared to young females, post-AOF females have increased plasmalemmal p47 phox SIG particles on non-AVP dendrites (Van Kempen et al 2015b).…”

“…At baseline, young females have a greater density of p47 phox SIG near the plasma membrane of AVP-containing dendrites than males m(Van Kempen et al 2015b). Compared to young females, post-AOF females have increased plasmalemmal p47 phox SIG particles on non-AVP dendrites (Van Kempen et al 2015b). Like males, slow pressor AngII elevates blood pressure in post-AOF females.…”

“…Like humans, a sex-dependent susceptibility to hypertension is seen in rodents following systemic administration of low doses of angiotensin II (AngII) via osmotic minipumps. In young male mice, but not cycling young female mice, systemic low-dose AngII-infusion results in a slowly developing increase in blood pressure (Girouard et al 2009, Li et al 2008, Marques-Lopes et al 2015a, Marques-Lopes et al 2014, Marques-Lopes et al 2015b, Pinkerton & Stovall 2010, Tiwari et al 2009, Van Kempen et al 2015b, Xue et al 2013, Xue et al 2005). However, slow-pressor AngII-infusion induces hypertension in OVX mice that model surgical menopause (Hay et al 2014, Xue et al 2013) and in aged rodents (Fortepiani et al 2003, Marques-Lopes et al 2015b, Tiwari et al 2009) that model the acyclicity (Nelson et al 1995) seen in post-menopause.…”

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

“…The subcellular distribution and density of NR2A-SIG particles in Darpp-32-labeled dendrites was determined as previously described (94). For this, the NR2A-SIG particle localization was categorized as (i) on plasma membrane, (ii) near plasma membrane (particles not touching but within 70 nm from the plasma membrane), or (iii) cytoplasmic.…”