title: Sex differences in NMDA GluN1 plasticity in rostral ventrolateral medulla neurons containing corticotropin-releasing factor type 1 receptor following slow-pressor angiotensin II hypertension.
abstract: There are profound, yet incompletely understood, sex differences in the neurogenic regulation of blood pressure. Both corticotropin signaling and glutamate receptor plasticity, which differ between males and females, are known to play important roles in the neural regulation of blood pressure. However, the relationship between hypertension and glutamate plasticity in corticotropin-releasing factor (CRF)-receptive neurons in brain cardiovascular regulatory areas, including the rostral ventrolateral medulla (RVLM) and paraventricular nucleus of the hypothalamus (PVN), is not understood. In the present study, we used dual-label immuno-electron microscopy to analyze sex differences in slow-pressor angiotensin II (AngII) hypertension with respect to the subcellular distribution of the obligatory NMDA glutamate receptor subunit 1 (GluN1) subunit of the N-methyl-D-aspartate receptor (NMDAR) in the RVLM and PVN. Studies were conducted in mice expressing the enhanced green fluorescence protein (EGFP) under the control of the CRF type 1 receptor (CRF1) promoter (i.e., CRF1-EGFP reporter mice). By light microscopy, GluN1-immunoreactivity (ir) was found in CRF1-EGFP neurons of the RVLM and PVN. Moreover, in both regions tyrosine hydroxylase (TH) was found in CRF1-EGFP neurons. In response to AngII, male mice showed an elevation in blood pressure that was associated with an increase in the proportion of GluN1 on presumably functional areas of the plasma membrane (PM) in CRF1-EGFP dendritic profiles in the RVLM. In female mice, AngII was neither associated with an increase in blood pressure nor an increase in PM GluN1 in the RVLM. Unlike the RVLM, AngII-mediated hypertension had no effect on GluN1 localization in CRF1-EGFP dendrites in the PVN of either male or female mice. These studies provide an anatomical mechanism for sex-differences in the convergent modulation of RVLM catecholaminergic neurons by CRF and glutamate. Moreover, these results suggest that sexual dimorphism in AngII-induced hypertension is reflected by NMDA receptor trafficking in presumptive sympathoexcitatory neurons in the RVLM.
authors: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st Street, New York, NY 10065, United States; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10021, United States.
authors: T A
authors: TA
authors: Van Kempen
authors: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st Street, New York, NY 10065, United States.
authors: M
authors: M
authors: Dodos
authors: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st Street, New York, NY 10065, United States.
authors: C
authors: C
authors: Woods
authors: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st Street, New York, NY 10065, United States.
authors: J
authors: J
authors: Marques-Lopes
authors: Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 1825 Pressler Street, Houston, TX 77030, United States.
authors: N J
authors: NJ
authors: Justice
authors: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st Street, New York, NY 10065, United States; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10021, United States.
authors: C
authors: C
authors: Iadecola
authors: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st Street, New York, NY 10065, United States; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10021, United States.
authors: V M
authors: VM
authors: Pickel
authors: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st Street, New York, NY 10065, United States; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10021, United States. Electronic address: mjg2003@med.cornell.edu.
authors: M J
authors: MJ
authors: Glass
authors: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st Street, New York, NY 10065, United States; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10021, United States; Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, United States. Electronic address: tmilner@med.cornell.edu.
authors: T A
authors: TA
authors: Milner
mesh_terms: D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D008297:Male; D008526:Medulla Oblongata / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics; D013266:Stilbamidines / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism / Q000648:ultrastructure; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D016194:Receptors, N-Methyl-D-Aspartate; D013266:Stilbamidines; D000804:Angiotensin II; D049452:Green Fluorescent Proteins; D000099052:CRF Receptor, Type 1; D014446:Tyrosine 3-Monooxygenase
keywords: C1 catecholaminergic neurons; catecholamine; electron microscopy; hypertension; paraventricular nucleus of the hypothalamus; sympathoexcitatory neurons