Membrane Trafficking of NADPH Oxidase p47phox in Paraventricular Hypothalamic Neurons Parallels Local Free Radical Production in Angiotensin II Slow-Pressor Hypertension

NADPH oxidase-generated reactive oxygen species (ROS) are highly implicated in the development of angiotensin II (AngII)-dependent hypertension mediated in part through the hypothalamic paraventricular nucleus (PVN). This region contains vasopressin and non-vasopressin neurons that are responsive to cardiovascular dysregulation, but it is not known whether ROS is generated by one or both cell types in response to “slow-pressor” infusion of AngII. We addressed this question using ROS imaging and electron microscopic dual labeling for vasopressin and p47phox, a cytoplasmic NADPH oxidase subunit requiring mobilization to membranes for the initiation of ROS production. C57BL/6 mice or vasopressin-enhanced green fluorescent protein (VP–eGFP) mice were infused systemically with saline or AngII (600 ng · kg−1 · min−1, s.c.) for 2 weeks, during which they slowly developed hypertension. Ultrastructural analysis of the PVN demonstrated p47phox immunolabeling in many glial and neuronal profiles, most of which were postsynaptic dendrites. Compared with saline, AngII recipient mice had a significant increase in p47phox immunolabeling on endomembranes just beneath the plasmalemmal surface (+42.1 ± 11.3%; p < 0.05) in non-vasopressin dendrites. In contrast, AngII infusion decreased p47phox immunolabeling on the plasma membrane (−35.5 ± 16.5%; p < 0.05) in vasopressin dendrites. Isolated non-VP–eGFP neurons from the PVN of AngII-infused mice also showed an increase in baseline ROS production not seen in VP–eGFP neurons. Our results suggest that chronic low-dose AngII may offset the homeostatic control of blood pressure by differentially affecting membrane assembly of NADPH oxidase and ROS production in vasopressin and non-vasopressin neurons located within the PVN.

• Publication year

  2013

• Venue

  Journal of Neuroscience

• Publication date

  2013-03-06

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1523/JNEUROSCI.3061-12.2013PMID 23467347PMCID PMC3616374
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Gene expression

  2019cited by this paper
• Reactive Oxygen Species

  2014cited by this paper
• Central Cardiovascular Circuits Contribute to the Neurovascular Dysfunction in Angiotensin II Hypertension

  2012cited by this paper
• Cyto‐ and chemoarchitecture of the hypothalamic paraventricular nucleus in the C57BL/6J male mouse: A study of immunostaining and multiple fluorescent tract tracing

  2012cited by this paper
• Renin–Angiotensin System Modulates Neurotransmitters in the Paraventricular Nucleus and Contributes to Angiotensin II-Induced Hypertensive Response

  2012cited by this paper
• Distribution of angiotensin type 1a receptor-containing cells in the brains of bacterial artificial chromosome transgenic mice.

  2012cited by this paper
• Endoplasmic reticulum–mitochondria coupling: local Ca2+ signalling with functional consequences

  2012cited by this paper
• Degenerating processes identified by electron microscopic immunocytochemical methods.

  2011cited by this paper
• Angiotensin-II-induced reactive oxygen species along the SFO-PVN-RVLM pathway: implications in neurogenic hypertension.

  2011cited by this paper
• The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension.

  2011cited by this paper
• Redox signaling (cross-talk) from and to mitochondria involves mitochondrial pores and reactive oxygen species.

  2010cited by this paper
• Chronic Intermittent Hypoxia Induces NMDA Receptor-Dependent Plasticity and Suppresses Nitric Oxide Signaling in the Mouse Hypothalamic Paraventricular Nucleus

  2010cited by this paper
• Increased vasopressin transmission from the paraventricular nucleus to the rostral medulla augments cardiorespiratory outflow in chronic intermittent hypoxia‐conditioned rats

  2010cited by this paper
• Glutamatergic synaptic transmission in neuroendocrine cells: Basic principles and mechanisms of plasticity.

  2010cited by this paper
• Specializations of gastrin‐releasing peptide cells of the mouse suprachiasmatic nucleus

  2009cited by this paper
• Molecular mechanisms of hypertension: role of Nox family NADPH oxidases.

  2009cited by this paper
• Oxidative stress in the sympathetic premotor neurons contributes to sympathetic activation in renovascular hypertension.

  2009influential reference
• Brain nuclear factor-kappa B activation contributes to neurohumoral excitation in angiotensin II-induced hypertension.

  2009cited by this paper
• NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation

  2009cited by this paper
• NMDA Receptor Activation Increases Free Radical Production through Nitric Oxide and NOX2

  2009cited by this paper
• NOX Enzymes in the Central Nervous System: From Signaling to Disease

  2009cited by this paper
• Distinct Domains within PSD-95 Mediate Synaptic Incorporation, Stabilization, and Activity-Dependent Trafficking

  2009cited by this paper
• Region-Specific Changes in the Subcellular Distribution of AMPA Receptor GluR1 Subunit in the Rat Ventral Tegmental Area after Acute or Chronic Morphine Administration

  2008cited by this paper
• Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase

  2008cited by this paper
• The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.

  2007influential reference
• Cyclooxygenase-2 Does Not Contribute to Postischemic Production of Reactive Oxygen Species

  2007cited by this paper
• Changes in the subcellular distribution of NADPH oxidase subunit p47phox in dendrites of rat dorsomedial nucleus tractus solitarius neurons in response to chronic administration of hypertensive agents.

  2007cited by this paper
• Subcellular localization of nicotinamide adenine dinucleotide phosphate oxidase subunits in neurons and astroglia of the rat medial nucleus tractus solitarius: relationship with tyrosine hydroxylase immunoreactive neurons.

  2006cited by this paper
• NADPH Oxidases of the Brain: Distribution, Regulation, and Function

  2006cited by this paper
• Nox2, Ca2+, and Protein Kinase C Play a Role in Angiotensin II–Induced Free Radical Production in Nucleus Tractus Solitarius

  2006cited by this paper
• Reactive oxygen species in the neuropathogenesis of hypertension

  2006cited by this paper
• Nox 2 , Ca 2 , and Protein Kinase C Play a Role in Angiotensin II – Induced Free Radical Production in Nucleus Tractus Solitarius

  2006cited by this paper
• Acute pressor effect of central angiotensin II is mediated by NAD(P)H-oxidase-dependent production of superoxide in the hypothalamic cardiovascular regulatory nuclei

  2006cited by this paper
• Superoxide Mediates Angiotensin II–Induced Influx of Extracellular Calcium in Neural Cells

  2005cited by this paper
• Expression and Modulation of an NADPH Oxidase in Mammalian Astrocytes

  2005cited by this paper
• Paraventricular nucleus, stress response, and cardiovascular disease

  2005cited by this paper
• NADPH Oxidase Contributes to Angiotensin II Signaling in the Nucleus Tractus Solitarius

  2004cited by this paper
• The mouse brain in stereotaxic coordinates

  2003cited by this paper
• A gene expression atlas of the central nervous system based on bacterial artificial chromosomes

  2003cited by this paper
• The hypothalamus and hypertension.

  2001cited by this paper
• Paraventricular nucleus neurons projecting to the spinal cord receive excitatory input from the subfornical organ.

  1995cited by this paper
• The functional expression of p47‐phox and p67‐phox may contribute to the generation of superoxide by an NADPH oxidase‐like system in human fibroblasts

  1994cited by this paper
• Involvement of adrenergic and angiotensinergic receptors in the paraventricular nucleus in the angiotensin II-induced vasopressin release.

  1992cited by this paper
• Flow Cytometric Analysis of Respiratory Burst Activity in Phagocytes With Hydroethidine and 2′,7′‐Dichlorofluorescin

  1990cited by this paper
• Glutamate, the dominant excitatory transmitter in neuroendocrine regulation.

  1990cited by this paper
• Vasopressin release to central and peripheral angiotensin II in rats with lesions of the subfornical organ.

  1984cited by this paper
• Role for the subfornical organ in vasopressin release.

  1984cited by this paper
• Release of vasopressin by angiotensin II.

  1975cited by this paper
• The Fine Structure of the Nervous System.

  1970cited by this paper
• The Fine Structure of the Nervous System

  1970cited by this paper
• J Am Soc Nephrol 13: 2860–2868, 2002 A Mouse Model of Angiotensin II Slow Pressor Response: Role of Oxidative Stress

  year unknowncited by this paper

• Research Progress on Central Regulatory Mechanisms of Acupuncture in Hypertension Treatment

  2025cites this paper
• Differing ionotropic glutamate receptor gene expression in paraventricular hypothalamic nucleus subregions following angiotensin II hypertension in male mice and female mice with advanced ovarian failure.

  2025cites this paper
• Tumor necrosis factor alpha induces NOX2-dependent reactive oxygen species production in hypothalamic paraventricular nucleus neurons following angiotensin II infusion.

  2024cites this paper
• Electroacupuncture and manual acupuncture at LR3 and ST36 have attenuating effects on hypertension and subsequent cognitive dysfunction in spontaneously hypertensive rats: A preliminary resting-state functional magnetic resonance imaging study

  2023cites this paper
• Intergenerational inheritance induced by a high-fat diet causes hyperphagia and reduced hypothalamic sensitivity to insulin and leptin in the second-generation of rats.

  2023cites this paper
• Blood pressure and cognitive function among older adults in India

  2022cites this paper
• Estrogen receptor beta activity contributes to both tumor necrosis factor alpha expression in the hypothalamic paraventricular nucleus and the resistance to hypertension following angiotensin II in female mice.

  2022cites this paper
• Angiotensin II infusion results in both hypertension and increased AMPA GluA1 signaling in hypothalamic paraventricular nucleus of male but not female mice.

  2022cites this paper
• Nrf1 Knock-Down in the Hypothalamic Paraventricular Nucleus Alleviates Hypertension Through Intervention of Superoxide Production-Removal Balance and Mitochondrial Function

  2021cites this paper
• DMSO_A_312527 2955..2972

  2021cites this paper
• Estrogen Receptor β Contributes to Both Hypertension and Hypothalamic Plasticity in a Mouse Model of Peri-Menopause

  2021cites this paper
• Nicotinamide Adenine Dinucleotide Phosphate Oxidases Are Everywhere in Brain Disease, but Not in Huntington’s Disease?

  2021cites this paper
• An Overview of Similarities and Differences in Metabolic Actions and Effects of Central Nervous System Between Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) and Sodium Glucose Co-Transporter-2 Inhibitors (SGLT-2is)

  2021cites this paper
• Tumor Necrosis Factor α Receptor Type 1 Activation in the Hypothalamic Paraventricular Nucleus Contributes to Glutamate Signaling and Angiotensin II-Dependent Hypertension

  2020cites this paper
• Oxycodone injections not paired with conditioned place preference have little effect on the hippocampal opioid system in female and male rats

  2020cites this paper
• The role of NADPH oxidases in neuronal development.

  2020cites this paper
• Association Between Blood Pressure and Later-Life Cognition Among Black and White Individuals.

  2020cites this paper
• Sex and age differentially affect GABAergic neurons in the mouse prefrontal cortex and hippocampus following chronic intermittent hypoxia.

  2019cites this paper
• Blood Pressure and Cognitive Decline Over 8 Years in Middle-Aged and Older Black and White Americans

  2019cites this paper
• Accelerated Ovarian Failure as a Unique Model to Study Peri-Menopause Influence on Alzheimer’s Disease

  2019cites this paper
• Plasma Membrane Affiliated AMPA GluA1 in Estrogen Receptor β-containing Paraventricular Hypothalamic Neurons Increases Following Hypertension in a Mouse Model of Post-menopause.

  2019cites this paper
• Sex Differences in the Rat Hippocampal Opioid System After Oxycodone Conditioned Place Preference.

  2018cites this paper
• Understanding the broad influence of sex hormones and sex differences in the brain

  2017influential citation
• Experimental Evidences Supporting Training-Induced Benefits in Spontaneously Hypertensive Rats.

  2017cites this paper
• Hypothalamic and inflammatory basis of hypertension.

  2017cites this paper
• Sex Differences in Neural Regulation of Hypertension

  2016cites this paper
• Subanesthetic isoflurane relieves zymosan-induced neutrophil inflammatory response by targeting NMDA glutamate receptor and Toll-like receptor 2 signaling

  2016cites this paper
• Alterations in the subcellular distribution of NADPH oxidase p47phox in hypothalamic paraventricular neurons following slow‐pressor angiotensin II hypertension in female mice with accelerated ovarian failure

  2016cites this paper
• 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

  2016cites this paper
• Adverse effects of tempol on hidrosaline balance in rats with acute sodium overload

  2016influential citation
• Sex differences in NMDA GluN1 plasticity in rostral ventrolateral medulla neurons containing corticotropin-releasing factor type 1 receptor following slow-pressor angiotensin II hypertension.

  2015influential citation
• 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

  2015influential citation
• NMDA Receptor Plasticity in the Hypothalamic Paraventricular Nucleus Contributes to the Elevated Blood Pressure Produced by Angiotensin II

  2015cites this paper
• Endothelial CD36 Contributes to Postischemic Brain Injury by Promoting Neutrophil Activation via CSF3

  2015cites this paper
• Autonomic Dysfunction, Sympathetic Hyperactivity and the Development of End-Organ Damage in Hypertension: Multiple Benefits of Exercise Training

  2015cites this paper
• Reactive oxygen species are involved in BMP-induced dendritic growth in cultured rat sympathetic neurons.

  2015cites this paper
• Hypothalamic Signaling Mechanisms in Hypertension

  2015cites this paper
• Slow‐pressor angiotensin II hypertension and concomitant dendritic NMDA receptor trafficking in estrogen receptor β–containing neurons of the mouse hypothalamic paraventricular nucleus are sex and age dependent

  2014cites this paper
• The angiotensin converting enzyme inhibitor captopril protects nigrostriatal dopamine neurons in animal models of parkinsonism.

  2013cites this paper
• production in hypothalamic paraventricular neurons NMDA currents and NOX2-dependent superoxide Angiotensin II slow-pressor hypertension enhances

  2013cites this paper
• Angiotensin II slow-pressor hypertension enhances NMDA currents and NOX2-dependent superoxide production in hypothalamic paraventricular neurons.

  2013cites this paper
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  2013cites this paper