title: 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 overactivity, upregulation of postsynaptic 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 postsynaptic 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 (600 ng/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 in 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 toward 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 (<1 µm) dendrites and decreased diameter of large (>1 µm) dendrites in females. Fluorescence microscopy revealed that AT1aR and estrogen receptor β do not colocalize, suggesting that if estrogen is involved, its effect is indirect. These 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 postsynaptic NMDA receptor trafficking.
authors.forename: Jose
authors.initials: J
authors.lastname: Marques-Lopes
authors.forename: Mary-Katherine
authors.initials: MK
authors.lastname: Lynch
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Van Kempen
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Waters
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Pickel
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Milner
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D003712:Dendrites / Q000378:metabolism* / Q000648:ultrastructure; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012084:Renin-Angiotensin System; D012737:Sex Factors
chemical_list: D047629:Estrogen Receptor beta; C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D016194:Receptors, N-Methyl-D-Aspartate; D000804:Angiotensin II