title: Redistribution of NMDA Receptors in Estrogen-Receptor-β-Containing Paraventricular Hypothalamic Neurons following Slow-Pressor Angiotensin II Hypertension in Female Mice with Accelerated Ovarian Failure.
abstract: Hypertension in male and aging female rodents is associated with glutamate-dependent plasticity in the hypothalamus, but existing models have failed to capture distinct transitional menopausal phases that could have a significant impact on the synaptic plasticity and emergent hypertension. In rodents, accelerated ovarian failure (AOF) induced by systemic injection of 4-vinylcyclohexane diepoxide mimics the estrogen fluctuations seen in human menopause including the perimenopause transition (peri-AOF) and postmenopause (post-AOF). Thus, we used the mouse AOF model to determine the impact of slow-pressor angiotensin II (AngII) administration on blood pressure and on the subcellular distribution of obligatory N-methyl-D-aspartate (NMDA) receptor GluN1 subunits in the paraventricular hypothalamic nucleus (PVN), a key estrogen-responsive cardiovascular regulatory area. Estrogen-sensitive neuronal profiles were identified in mice expressing enhanced green fluorescent protein under the promoter for estrogen receptor (ER) β, a major ER in the PVN. Slow-pressor AngII increased arterial blood pressure in mice at peri- and post-AOF time points. In control oil-injected (nonhypertensive) mice, AngII decreased the total number of GluN1 in ERβ-containing PVN dendrites. In contrast, AngII resulted in a reapportionment of GluN1 from the cytoplasm to the plasma membrane of ERβ-containing PVN dendrites in peri-AOF mice. Moreover, in post-AOF mice, AngII increased total GluN1, dendritic size and radical production in ERβ-containing neurons. These results indicate that unique patterns of hypothalamic glutamate receptor plasticity and dendritic structure accompany the elevated blood pressure in peri- and post-AOF time points. Our findings suggest the possibility that distinct neurobiological processes are associated with the increased blood pressure during perimenopausal and postmenopausal periods.
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, N.Y., USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Marques-Lopes
authors.forename: Ephrath
authors.initials: E
authors.lastname: Tesfaye
authors.forename: Sigal
authors.initials: S
authors.lastname: Israilov
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Van Kempen
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Glass
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Pickel
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Waters
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Milner
mesh_terms: D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D053138:Cyclohexenes / Q000633:toxicity; D004195:Disease Models, Animal; D030762:Estrous Cycle / Q000187:drug effects / Q000235:genetics; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000150:complications / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D010049:Ovarian Diseases / Q000209:etiology*; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D014753:Vinyl Compounds / Q000633:toxicity
chemical_list: D053138:Cyclohexenes; C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D016194:Receptors, N-Methyl-D-Aspartate; D014753:Vinyl Compounds; C107914:estrogen receptor-related receptor beta; D000804:Angiotensin II; D049452:Green Fluorescent Proteins; C012606:4-vinyl-1-cyclohexene dioxide