After menopause, hypertension and cardiovascular risk increases in women. Our preliminary data indicate that a comparable susceptibility to hypertension can be observed following slow pressor angiotensin II (AngII) infusion in a menopausal mouse model. The hypothalamic paraventricular nucleus (PVN) is critical for integrating and coordinating neurohumoral responses involved in cardiovascular regulation. In hypertension, NMDA receptor activation and NADPH oxidase-dependent reactive oxygen species (ROS) production in PVN neurons that project to the spinal cord plays a pivotal role in enhancing the sympathetic drive that underlies the elevation of arterial pressure. A significant number of PVN-spinal neurons contain the estrogen receptor (ER) ?, suggesting that hormone alterations in menopause could selectively influence excitation in this population. In particular, gonadal steroids could alter excitatory transmission by regulating the expression and/or subcellular distribution of the NMDA receptor, voltage-gated Ca2+ channel currents and/or the generation of NADPH oxidase derived ROS. Such changes could ultimately contribute to the development of hypertension observed in menopause. Therefore, this proposal will test the central hypothesis that changes in postsynaptic NMDA receptors and associated signaling pathways within ER? PVN neurons during menopause predisposes these neurons to increase excitability in response to hypertensive challenges.
Two aims will examine mouse models of menopause to determine (1) whether menopause increases the susceptibility to slow pressor AngII hypertension through mechanisms involving post-synaptic NMDA receptors in the PVN;and (2) if NMDA-mediated responses in ER?-containing PVN neurons show adaptations consistent with the potentiation of excitatory transmission during the development of hypertension. These studies will be conducted in the well-established intact aging model and the new VCD model of menopause including some ER?-GFP transgenic mice, and will use slow pressor AngII- infusion as the hypertensive challenge. These studies will be achieved using a multidisciplinary approach including high resolution electron microscopic immunolabeling to identify the subcellular distribution of essential NMDA NR1 receptors and related signaling pathway components in ER?-GFP labeled PVN neurons, spatial-temporal deletion of the NR1 gene, quantitative RT-PCR, patch-clamp recording, ROS imaging, and telemetric measurement of blood pressure.

Public Health Relevance

Young women are less susceptible to developing hypertension than their male counterparts. However, during menopause women develop an increased incidence of hypertension and related cerebrovascular complications that can surpass that of men. The proposed studies will provide novel information about the neurobiology of a cardiovascular hypothalamic circuit that is particularly sensitive to fluctuations in hormone levels that may significantly contribute to increased susceptibility to hypertension. Moreover, they may provide the mechanistic basis for developing more effective therapeutic strategies for the management of post-menopausal increases in blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098351-02
Application #
8230454
Study Section
Special Emphasis Panel (ZRG1-IFCN-C (04))
Program Officer
Maric-Bilkan, Christine
Project Start
2011-02-15
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$422,500
Indirect Cost
$172,500
Name
Weill Medical College of Cornell University
Department
Neurology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Ryan, James D; Zhou, Yan; Contoreggi, Natalina H et al. (2018) Sex Differences in the Rat Hippocampal Opioid System After Oxycodone Conditioned Place Preference. Neuroscience 393:236-257
McAlinn, Helena R; Reich, Batsheva; Contoreggi, Natalina H et al. (2018) Sex Differences in the Subcellular Distribution of Corticotropin-Releasing Factor Receptor 1 in the Rat Hippocampus following Chronic Immobilization Stress. Neuroscience 383:98-113
Ma, Qian; Yang, Jianmin; Milner, Teresa A et al. (2017) SorCS2-mediated NR2A trafficking regulates motor deficits in Huntington's disease. JCI Insight 2:
McEwen, Bruce S; Milner, Teresa A (2017) Understanding the broad influence of sex hormones and sex differences in the brain. J Neurosci Res 95:24-39
Burgdorf, Caitlin E; Schierberl, Kathryn C; Lee, Anni S et al. (2017) Extinction of Contextual Cocaine Memories Requires Cav1.2 within D1R-Expressing Cells and Recruits Hippocampal Cav1.2-Dependent Signaling Mechanisms. J Neurosci 37:11894-11911
Zille, Marietta; Karuppagounder, Saravanan S; Chen, Yingxin et al. (2017) Neuronal Death After Hemorrhagic Stroke In Vitro and In Vivo Shares Features of Ferroptosis and Necroptosis. Stroke 48:1033-1043
Marques-Lopes, Jose; Tesfaye, Ephrath; Israilov, Sigal et al. (2017) Redistribution of NMDA Receptors in Estrogen-Receptor-?-Containing Paraventricular Hypothalamic Neurons following Slow-Pressor Angiotensin II Hypertension in Female Mice with Accelerated Ovarian Failure. Neuroendocrinology 104:239-256
Rogers, Sophie A; Kempen, Tracey A Van; Pickel, Virginia M et al. (2016) Enkephalin levels and the number of neuropeptide Y-containing interneurons in the hippocampus are decreased in female cannabinoid-receptor 1 knock-out mice. Neurosci Lett 620:97-103
Chung, Sun Young; Kishinevsky, Sarah; Mazzulli, Joseph R et al. (2016) Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and ?-Synuclein Accumulation. Stem Cell Reports 7:664-677
Mende, Michael; Fletcher, Emily V; Belluardo, Josephine L et al. (2016) Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord. Neuron 90:1189-1202

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