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
Almey, Anne; Milner, Teresa A; Brake, Wayne G (2016) Estrogen receptor α and G-protein coupled estrogen receptor 1 are localized to GABAergic neurons in the dorsal striatum. Neurosci Lett 622:118-23
Van Kempen, Tracey A; Narayan, Ankita; Waters, Elizabeth M et al. (2016) 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. J Comp Neurol 524:2251-65
Chung, Sun Young; Kishinevsky, Sarah; Mazzulli, Joseph R et al. (2016) Parkin and PINK1 Patient iPSC-Derived Midbrain Dopamine Neurons Exhibit Mitochondrial Dysfunction and α-Synuclein Accumulation. Stem Cell Reports 7:664-677
Mazid, Sanoara; Hall, Baila S; Odell, Shannon C et al. (2016) Sex differences in subcellular distribution of delta opioid receptors in the rat hippocampus in response to acute and chronic stress. Neurobiol Stress 5:37-53
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
Mende, Michael; Fletcher, Emily V; Belluardo, Josephine L et al. (2016) Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord. Neuron 90:1189-202
Marques-Lopes, Jose; Lynch, Mary-Katherine; Van Kempen, Tracey A et al. (2015) 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. Synapse 69:148-65
Ma, Qian; Yang, Jianmin; Li, Thomas et al. (2015) Selective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington's disease. Neurobiol Dis 82:466-77
Waters, Elizabeth M; Thompson, Louisa I; Patel, Parth et al. (2015) G-protein-coupled estrogen receptor 1 is anatomically positioned to modulate synaptic plasticity in the mouse hippocampus. J Neurosci 35:2384-97
Van Kempen, T A; Dodos, M; Woods, C et al. (2015) Sex differences in NMDA GluN1 plasticity in rostral ventrolateral medulla neurons containing corticotropin-releasing factor type 1 receptor following slow-pressor angiotensin II hypertension. Neuroscience 307:83-97

Showing the most recent 10 out of 35 publications