Abstract 33: Endoplasmic Reticulum Stress and Vascular Dysfunction in Hypertension

Objective: Cardiac damage and vascular dysfunction are major causes of morbidity and mortality in hypertension. In this study, we explored the beneficial therapeutic effect of endoplasmic reticulum (ER) stress inhibition on cardiac damage and vascular dysfunction in hypertension. Methods & results: Mice were infused with angiotensin II (Ang-II, 400 ng/kg/min) with or without ER stress inhibitors (Tudca and PBA) for two weeks. Mice infused with Ang-II displayed an increase in blood pressure, cardiac hypertrophy and fibrosis associated with enhanced collagen-I content, TGFβ1 activity, and ER stress markers, which were blunted after ER stress inhibition. Hypertension induced ER stress in aorta and mesenteric resistance arteries (MRA), enhanced TGFβ1 activity in aorta but not in MRA, and reduced eNOS phosphorylation and endothelium-dependent relaxation (EDR) in aorta and MRA. The inhibition of ER stress significantly reduced TGFβ1 activity, enhanced eNOS phosphorylation and improved EDR. The inhibition of TGFβ1 pathway improved EDR in aorta but not in MRA, while the reduction in ROS levels ameliorated EDR in MRA only. Infusion of tunicamycin in control mice induced ER stress in aorta and MRA, and reduced EDR by a TGFβ1-dependent mechanism in aorta and ROS-dependent mechanism in MRA. Conclusion: ER stress inhibition reduces cardiac damage and improves vascular function in hypertension. Therefore ER stress could be a potential target for cardiovascular diseases.

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Abstract P217: Nox Compartmentalization, Protein Oxidation and ER Stress in Vascular Smooth Muscle Cells in Hypertension

Hypertension ◽

10.1161/hyp.70.suppl_1.p217 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Livia L Camargo ◽

Augusto C Montezano ◽

Adam Harvey ◽

Sofia Tsiropoulou ◽

Katie Hood ◽

...

Keyword(s):

Er Stress ◽

Protein Oxidation ◽

Vascular Function ◽

Vascular Reactivity ◽

Stress Proteins ◽

Vascular Dysfunction ◽

Mesenteric Arteries ◽

Resistance Arteries ◽

Post Translational Modification ◽

Wistar Kyoto

In hypertension, activation of NADPH oxidases (Noxs) is associated with oxidative stress and vascular dysfunction. The exact role of each isoform in hypertension-associated vascular injury is still unclear. We investigated the compartmentalization of Noxs in VSMC from resistance arteries of Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Expression of Nox1 and Nox4 was increased in SHR cells (96.6±28.7% and 48.2±21.2% vs WKY, p<0.05), as well as basal ROS levels measured by chemiluminescence (110.2±26.4% vs WKY, p<0.05) and amplex red (105.2±33.2% vs WKY, p<0.05). Phosphorylation of unfolded protein response activators, PERK and IRE1α, and expression of ER chaperone BiP were elevated in SHR cells (p<0.05 vs WKY), indicating activation of ER stress response. Immunoblotting after organelle fractionation demonstrated that Noxs are expressed in an organelle-specific manner, with Nox1, 2 and 4 present in plasma membrane, ER and nucleus, but not in mitochondria. In SHR cells, NoxA1ds (Nox1 inhibitor, 10μM) and GKT136901 (Nox1/4 inhibitor, 10μM) decreased AngII-induced ROS levels (p<0.001 vs Ctl). Additionally, mito-tempol (mitochondrial-targeted antioxidant, 50nM) and 4-PBA (ER stress inhibitor, 1mM) decreased basal ROS levels in SHR cells (p<0.05 vs Ctl). Furthermore, oxidation of the antioxidant enzymes Peroxiredoxins (Prx) was increased in SHRSP compared to WKY (2.51±0.14 vs 0.56±0.07, p<0.001). One-dimensional isoelectric focusing revealed that cytosolic Prx2 and mitochondrial Prx3 were more oxidized in SHRSP than WKY cells. Using a biotin-tagged dimedone-based probe (DCP-Bio) we identified oxidation of ER stress proteins BiP and IRE1. To investigate the effect of protein oxidation in vascular function, vascular reactivity was evaluated in isolated mesenteric arteries. Inhibition of general oxidation (DTT 1mM; Emax: 111.7±33.1) and peroxiredoxin (Conoidin A 10nM; Emax: 116.0±7.3) reduces vascular contraction in response to noradrenalin in WKY rats (Emax: 166.6±30.2; p<0.05). These findings suggest an important role for Nox1/4 in redox-dependent organelle dysfunction and post-translational modification of proteins, processes that may play an important role in vascular dysfunction in hypertension.

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Abstract MP59: Soluble Protein Oligomers Induce Endoplasmic Reticulum Stress In Mesenteric Resistance Arteries From Male And Female Mice

Hypertension ◽

10.1161/hyp.78.suppl_1.mp59 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Emily W Waigi ◽

Thaddaeus R Castaneda ◽

Nicole R Bearss ◽

Jonnelle M Edwards ◽

David R Giovannucci ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Vascular System ◽

Vascular Dysfunction ◽

Amyloid Β ◽

Positive Control ◽

Resistance Arteries ◽

Male And Female ◽

Female Mice ◽

Antibody Staining

Amyloid β proteins, including toxic soluble oligomers (SPOs) are not only found in the brain duringAlzheimer’s, but also in the peripheral vascular system. The precise mechanism linking increasedcirculating levels of SPOs and vascular dysfunction remains unknown. We hypothesized that SPOslead to endoplasmic reticulum (ER) stress, further release of SPOs and vascular injury. Mesentericresistance arteries (MRAs) from 14 weeks old, male and female C57BL/6 mice were used forvascular function. Agonists were acetylcholine and phenylephrine (1nM-10mM). In acuteconditions, SPOs (0.1μM) caused pathologically exacerbated endothelium-dependent vasodilationcompared to vehicle (F12 media) [Male: EC50: SPOs: -7.0 ± 0.1 (n=4), vs. Vehicle -6.6 ± 0.1 (n=7)p=0.03; Female: EC50: SPOs: -7.3 ± 0.06 (n=5) vs. Vehicle -6.7 ± 0.1 (n=6), p=0.001]. Thisphenotype was similar to the positive control tunicamycin (5mg/ml) [Male: EC50: Tunicamycin: -7.3(n=4), vs. Vehicle -6.6 (n=7) p=0.2; Female: EC50: Tunicamycin: -7.7 (n=4) vs. Vehicle -6.8 (n=5)p=0.04]. To determine whether SPO’s cause ER stress, arteries were treated with ER stressinhibitor 4-Phenylbutyric acid (2mM). The ER stress inhibitor prevented the exacerbatedvasodilation induced by SPOs showing SPOs trigger ER stress in acute conditions independent ofsex. To determine whether SPOs are a consequence of ER stress, arteries were incubated withtunicamycin in the presence of the SPO inhibitor K01-162 (10mM). Interestingly, K01-162 did notprevent the tunicamycin-induced exacerbated vasodilation in arteries from male mice. However,this response was decreased in arteries from female mice showing that inducing ER stress leadsto the release of SPOs, escalating a feed-forward mechanism of further SPO release. There wereno changes in vascular contraction with tunicamycin or SPOs irrespective of sex. ER stress wasconfirmed with anti-KDEL antibody staining, specific for ER resident chaperones Grp78/94 andvisualized with multiphoton fluorescent confocal microscopy. These results demonstrate that SPO’sexacerbate endothelium-dependent vasodilation acutely and may contribute to brain and peripheralvascular edema and loss of autoregulation observed during cardiovascular and Alzheimer’sdisease.

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Abstract P213: Vascular Dysfunction and Aberrant Vascular NOTCH3 Signalling in Hypertension and Cerebral Autosomal Dominant Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Hypertension ◽

10.1161/hyp.68.suppl_1.p213 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Adam Harvey ◽

Fiona Moreton ◽

Augusto C Montezano ◽

Aurelie Nguyen Dinh Cat ◽

Paul Rocchiccioli ◽

...

Keyword(s):

Er Stress ◽

Vascular Function ◽

Small Vessel Disease ◽

Vascular Dysfunction ◽

Gene Array ◽

Rho Kinase ◽

Small Vessel ◽

Vessel Disease ◽

Stress Markers ◽

Clinical Conditions

Hypertension (HT) and CADASIL are clinical conditions of small vessel disease. Vascular dementia is a major feature in CADASIL, and a serious consequence of HT. CADASIL is a monogenic condition due to mutations in NOTCH3 , which is expressed almost exclusively in VSMCs. We hypothesised that altered NOTCH3 signalling in CADASIL and HT are associated with small vessel disease. Small arteries from gluteal biopsies from CADASIL patients (n=14), HT patients (n=3) and healthy controls (n=10) were investigated. Vascular function was assessed by myography. Cultured VSMCs were used to assess signaling through NOTCH3, NO, ER stress (gene array) and Rho kinase (ELISA). CADASIL and HT patients exhibited endothelial dysfunction (Max response: CADASIL 41.7±3%, HT 54.1±2% vs Control 98.2±4%). Pre-incubation with N-acetyl-cysteine ameliorated vasorelaxation. Only CADASIL displayed impaired endothelium-independent relaxation (Max response: CADASIL 53±1.9% vs Control 93±8.9%) and contraction (Max response: CADASIL 78±1.3% vs control 102±5%) (p<0.05). AngII-induced contraction was elevated in HT (98%), yet reduced in CADASIL (28%) (vs control 64% max contraction: p<0.05), despite VSMCs from both conditions displaying increased AT 1 R mRNA expression (HT: 5.1; CADASIL: 3.8; fold vs control; p<0.05). VSMCs from CADASIL and HT have decreased expression of CAMK1, SIRT2 and VEGFA; important in NO signalling (0.5 fold; p<0.05 vs control). VSMC levels of NOTCH3 and NOTCH ligand, JAG1, were increased in CADASIL (3.5, 2.5 fold) and HT (3.0, 2.6 fold, p<0.05). Downstream targets, HEY1 and HEYL, were elevated in CADASIL (3.8, 4.2 fold) and HT (1.9, 2.6 fold) (p<0.05). CADASIL but not HT VSMCs exhibited increased expression of ER stress markers. Rho kinase activity was increased in VSMCs from CADASIL (2.5 fold) and HT (2 fold) vs control (p<0.05). These data demonstrate that in CADASIL and HT, vascular dysfunction, is associated with aberrant NOTCH3 and Rho kinase signalling. In CADASIL, but not HT, endothelium-independent relaxation and ER stress were increased. Our results demonstrate a putative role for NOTCH3 -Rho kinase in vascular dysfunction in conditions of small vessel disease and suggest that ER stress and oxidative stress may be important in vascular injury in CADASIL.

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Abstract 143: Endoplasmic Reticulum Stress Impairs Vascular Function Through Enhanced Nadph Oxidase Activity and Reduction in Enos Activity

Hypertension ◽

10.1161/hyp.60.suppl_1.a143 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Maria Galan ◽

Modar Kassan ◽

Mohamed Trebak ◽

Khalid Matrougui

Keyword(s):

Endoplasmic Reticulum ◽

Nadph Oxidase ◽

Er Stress ◽

P38 Mapk ◽

Vascular Function ◽

Oxidase Activity ◽

Mrna Levels ◽

Stress Induction ◽

Nadph Oxidase Activity ◽

Enos Phosphorylation

Cardiovascular diseases are associated with the induction of endoplasmic reticulum (ER) stress. The induction of ER stress in C57BL/6J and p47phox-/- mice, by the injection of tunicamycin, greatly impaired vascular endothelium-dependent relaxation in C57BL/6J than in p47phox-/- mice. To determine the mechanism by which ER stress impairs endothelium function, we incubated mice primary endothelial cells from coronary arteries (ECs) with tunicamycin (1 μg/mL) for 6 h in the presence or absence of two ER stress inhibitors (Tudca, 500 μg/mL and PBA, 10 mM). Tunicamycin increased the phosphorylation of PERK and eIF2alpha, the expression of CHOP, ATF6 and Bip, Nox2/Nox4 mRNA levels, NADPH oxidase activity and superoxide anion levels. In addition, phosphorylated eNOS and nitrites levels were reduced with tunicamycin. All these events were prevented, at least partially, with the inhibition of ER stress. Tunicamycin treatment or the transfection of ECs with plasmids that express ATF6 or CHOP reduced the luciferase activity of a reporter plasmid containing the eNOS promoter. The ER stress induction reduced ERK1/2 phosphorylation and increased p38 MAPK phosphorylation. The inhibition of p38 MAPK restored the eNOS promoter activity and the eNOS phosphorylation, and reduced Bip but did not affect to ATF6 or CHOP expression. Conclusion: ER stress induction impairs endothelial cell eNOS-dependent activity by oxidative stress and p38 MAPK-dependent mechanisms.

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EGFRvIII Promotes Cell Survival during Endoplasmic Reticulum Stress through a Reticulocalbin 1-Dependent Mechanism

Cancers ◽

10.3390/cancers13061198 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1198

Author(s):

Juliana Gomez ◽

Zammam Areeb ◽

Sarah F. Stuart ◽

Hong P. T. Nguyen ◽

Lucia Paradiso ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Viability ◽

Er Stress ◽

Cell Survival ◽

Glioblastoma Cells ◽

Over Expression ◽

Stress Markers ◽

Apoptotic Protein ◽

Novel Association ◽

Reduced Activity

Reticulocalbin 1 (RCN1) is an endoplasmic reticulum (ER)-residing protein, involved in promoting cell survival during pathophysiological conditions that lead to ER stress. However, the key upstream receptor tyrosine kinase that regulates RCN1 expression and its potential role in cell survival in the glioblastoma setting have not been determined. Here, we demonstrate that RCN1 expression significantly correlates with poor glioblastoma patient survival. We also demonstrate that glioblastoma cells with expression of EGFRvIII receptor also have high RCN1 expression. Over-expression of wildtype EGFR also correlated with high RCN1 expression, suggesting that EGFR and EGFRvIII regulate RCN1 expression. Importantly, cells that expressed EGFRvIII and subsequently showed high RCN1 expression displayed greater cell viability under ER stress compared to EGFRvIII negative glioblastoma cells. Consistently, we also demonstrated that RCN1 knockdown reduced cell viability and exogenous introduction of RCN1 enhanced cell viability following induction of ER stress. Mechanistically, we demonstrate that the EGFRvIII-RCN1-driven increase in cell survival is due to the inactivation of the ER stress markers ATF4 and ATF6, maintained expression of the anti-apoptotic protein Bcl-2 and reduced activity of caspase 3/7. Our current findings identify that EGFRvIII regulates RCN1 expression and that this novel association promotes cell survival in glioblastoma cells during ER stress.

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The effect of baicalein on endoplasmic reticulum stress and autophagy on liver damage

Human & Experimental Toxicology ◽

10.1177/09603271211003634 ◽

2021 ◽

pp. 096032712110036

Author(s):

MC Üstüner ◽

C Tanrikut ◽

D Üstüner ◽

UK Kolaç ◽

Z Özdemir Köroğlu ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Transcription Factor ◽

Er Stress ◽

Liver Damage ◽

Albino Rats ◽

Tem Analysis ◽

Stress Markers ◽

Activating Transcription Factor 4 ◽

Activating Transcription Factor ◽

Wistar Albino Rats

Carbon tetrachloride (CCl4) is a toxic chemical that causes liver injury. CCl4 triggers endoplasmic reticulum (ER) stress and unfolded protein response (UPR). UPR triggers autophagy to deal with the damage. The aim of this study was to investigate the effect of baicalein, derived from Scutellaria baicalensis, on CCl4-induced liver damage concerning ER stress and autophagy. Two groups of Wistar albino rats (n = 7/groups) were treated with 0.2 ml/kg CCl4 for 10 days with and without baicalein. Histological and transmission electron microscopy (TEM) analysis, autophagy, and ER stress markers measurements were carried out to evaluate the effect of baicalein. Histological examinations showed that baicalein reduced liver damage. TEM analysis indicated that baicalein inhibited ER stress and triggered autophagy. CCl4-induced elevation of C/EBP homologous protein (CHOP), glucose-regulating protein 78 (GRP78), activating transcription factor 4 (ATF4), activating transcription factor 6 (ATF6), inositol requiring enzyme 1 (IRE1), pancreatic ER kinase (PERK), and active/spliced form of X-box-binding protein 1 (XBP1s) ER stress markers were decreased by baicalein. Baicalein also increased the autophagy-related 5 (ATG5), Beclin1, and Microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine-conjugated form (LC3-II) autophagy marker levels. In conclusion, baicalein reduced the CCl4-induced liver damage by inhibiting ER stress and the trigger of autophagy.

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Coptisine Attenuates Diabetes—Associated Endothelial Dysfunction through Inhibition of Endoplasmic Reticulum Stress and Oxidative Stress

Molecules ◽

10.3390/molecules26144210 ◽

2021 ◽

Vol 26 (14) ◽

pp. 4210

Author(s):

Yan Zhou ◽

Chunxiu Zhou ◽

Xutao Zhang ◽

Chi Teng Vong ◽

Yitao Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Risk Factors ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Vascular Function ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Ex Vivo ◽

Diabetic Mice ◽

And Oxidative Stress

Coptisine is the major bioactive protoberberine alkaloid found in Rhizoma Coptidis. Coptisine reduces inflammatory responses and improves glucose tolerance; nevertheless, whether coptisine has vasoprotective effect in diabetes is not fully characterized. Conduit arteries including aortas and carotid arteries were obtained from male C57BL/6J mice for ex vivo treatment with risk factors (high glucose or tunicamycin) and coptisine. Some arterial rings were obtained from diabetic mice, which were induced by high-fat diet (45% kcal% fat) feeding for 6 weeks combined with a low-dose intraperitoneal injection of streptozotocin (120 mg/kg). Functional studies showed that coptisine protected endothelium-dependent relaxation in aortas against risk factors and from diabetic mice. Coptisine increased phosphorylations of AMPK and eNOS and downregulated the endoplasmic reticulum (ER) stress markers as determined by Western blotting. Coptisine elevates NO bioavailability and decreases reactive oxygen species level. The results indicate that coptisine improves vascular function in diabetes through suppression of ER stress and oxidative stress, implying the therapeutic potential of coptisine to treat diabetic vasculopathy.

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Acute Tissue Injury Caused by Subcutaneous Fat Biopsies Produces Endoplasmic Reticulum Stress

Endocrine Reviews ◽

10.1210/edrv.30.7.9995 ◽

2009 ◽

Vol 30 (7) ◽

pp. 928-928

Author(s):

Guenther Boden ◽

Matthew Silviera ◽

Brian Smith ◽

Peter Cheung ◽

Carol Homko

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Tissue Injury ◽

Subcutaneous Fat ◽

Whole Body ◽

Monocyte Chemoattractant Protein 1 ◽

Homologous Protein ◽

Stress Markers ◽

Acute Tissue Injury ◽

Glucose Regulated Protein

Abstract Background It is not known whether acute tissue injury is associated with endoplasmic reticulum (ER) stress. Objective Our objective was to determine whether open, sc fat biopsies cause ER stress. Approach Five healthy subjects underwent three open sc fat biopsies. The first biopsy, taken from the lateral aspect of a thigh, was followed 4 h later by a second biopsy from the same incision site and a third biopsy from the contralateral leg. Expression markers of ER stress, inflammation, hypoxia, and adipokines were measured in these fat biopsies. In addition, we tested for signs of systemic ER stress and inflammation in plasma and in circulating monocytes. Results mRNA/18s ratios of IL-6, monocyte chemoattractant protein-1, CD-14, hypoxia-induced factor 1-α, the spliced form of Xbox protein-1, glucose-regulated protein 78, CEBP homologous protein, and activating factor-4 were all severalfold higher, whereas mRNA/18s ratios of adiponectin and leptin were lower in fat biopsies taken from the same site 4 h after the first biopsy but were unchanged in the second biopsy that was taken from the contralateral site. The biopsies were not associated with changes in plasma and monocyte IL-6 concentrations or in monocyte ER stress markers. Also, whole-body insulin-stimulated glucose uptake was the same in 15 subjects who had biopsies compared with 15 different subjects who did not. Conclusion Open, sc fat biopsies produced inflammation, hypoxia, ER stress, and decreased expression of adiponectin and leptin. These changes remained confined to the biopsy site for at least 4 h.

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Attenuation of endoplasmic reticulum stress by caffeine ameliorates hyperoxia-induced lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00405.2016 ◽

2017 ◽

Vol 312 (5) ◽

pp. L586-L598 ◽

Cited By ~ 38

Author(s):

Ru-Jeng Teng ◽

Xigang Jing ◽

Teresa Michalkiewicz ◽

Adeleye J. Afolayan ◽

Tzong-Jin Wu ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Lung Injury ◽

Er Stress ◽

Saline Control ◽

Sprague Dawley ◽

Chemical Chaperone ◽

Stress Markers ◽

Rat Pups ◽

Caffeine Treatment ◽

Downstream Effectors

Rodent pups exposed to hyperoxia develop lung changes similar to bronchopulmonary dysplasia (BPD) in extremely premature infants. Oxidative stress from hyperoxia can injure developing lungs through endoplasmic reticulum (ER) stress. Early caffeine treatment decreases the rate of BPD, but the mechanisms remain unclear. We hypothesized that caffeine attenuates hyperoxia-induced lung injury through its chemical chaperone property. Sprague-Dawley rat pups were raised either in 90 (hyperoxia) or 21% (normoxia) oxygen from postnatal day 1 (P1) to postnatal day 10 (P10) and then recovered in 21% oxygen until P21. Caffeine (20 mg/kg) or normal saline (control) was administered intraperitoneally daily starting from P2. Lungs were inflation-fixed for histology or snap-frozen for immunoblots. Blood caffeine levels were measured in treated pups at euthanasia and were found to be 18.4 ± 4.9 μg/ml. Hyperoxia impaired alveolar formation and increased ER stress markers and downstream effectors; caffeine treatment attenuated these changes at P10. Caffeine also attenuated the hyperoxia-induced activation of cyclooxygenase-2 and markers of apoptosis. In conclusion, hyperoxia-induced alveolar growth impairment is mediated, in part, by ER stress. Early caffeine treatment protects developing lungs from hyperoxia-induced injury by attenuating ER stress.

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Endoplasmic reticulum and oxidant stress mediate nuclear factor-κB activation in the subfornical organ during angiotensin II hypertension

AJP Cell Physiology ◽

10.1152/ajpcell.00223.2014 ◽

2015 ◽

Vol 308 (10) ◽

pp. C803-C812 ◽

Cited By ~ 20

Author(s):

Colin N. Young ◽

Anfei Li ◽

Frederick N. Dong ◽

Julie A. Horwath ◽

Catharine G. Clark ◽

...

Keyword(s):

Blood Pressure ◽

Endoplasmic Reticulum ◽

Transcription Factor ◽

Angiotensin Ii ◽

Er Stress ◽

Bioluminescence Imaging ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Ang Ii ◽

Arterial Blood

Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in the brain circumventricular subfornical organ (SFO) mediate the central hypertensive actions of Angiotensin II (ANG II). However, the downstream signaling events remain unclear. Here we tested the hypothesis that angiotensin type 1a receptors (AT1aR), ER stress, and ROS induce activation of the transcription factor nuclear factor-κB (NF-κB) during ANG II-dependent hypertension. To spatiotemporally track NF-κB activity in the SFO throughout the development of ANG II-dependent hypertension, we used SFO-targeted adenoviral delivery and longitudinal bioluminescence imaging in mice. During low-dose infusion of ANG II, bioluminescence imaging revealed a prehypertensive surge in NF-κB activity in the SFO at a time point prior to a significant rise in arterial blood pressure. SFO-targeted ablation of AT1aR, inhibition of ER stress, or adenoviral scavenging of ROS in the SFO prevented the ANG II-induced increase in SFO NF-κB. These findings highlight the utility of bioluminescence imaging to longitudinally track transcription factor activation during the development of ANG II-dependent hypertension and reveal an AT1aR-, ER stress-, and ROS-dependent prehypertensive surge in NF-κB activity in the SFO. Furthermore, the increase in NF-κB activity before a rise in arterial blood pressure suggests a causal role for SFO NF-κB in the development of ANG II-dependent hypertension.

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