Flow-mediated vasodilation is impaired in adult rat offspring exposed to prenatal hypoxia

2011 ◽  
Vol 110 (4) ◽  
pp. 1073-1082 ◽  
Author(s):  
J. S. Morton ◽  
C. F. Rueda-Clausen ◽  
S. T. Davidge
Keyword(s):  
Cardiovascular Diseases ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Female Offspring ◽  
Mesenteric Arteries ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Adult Rat ◽  
Increased Risk ◽  
The Impact

There is now a demonstrated association between low birth weight and increased mortality later in life. Changes in fetal development may program the cardiovascular system and lead to an increased risk of cardiovascular diseases later in life. In addition, aging is a risk factor for vascular endothelial-dependent dysfunction. However, the impact of being born intrauterine growth restricted (IUGR) on the normal aging mechanisms of vascular dysfunction is not clear. We hypothesized that IUGR would cause changes in vascular function that would affect the mechanisms of flow-induced vasodilation later in life in an age- or sex-dependent manner. To create an IUGR model, pregnant Sprague-Dawley rats were placed in a hypoxic (11.5% O2) or control (room air, 21% O2) environment from days 15 to 21 of pregnancy. Both male and female offspring were investigated at 4 or 12 mo of age. Vascular function was assessed in small mesenteric arteries using flow-induced vasodilation, a physiological stimuli of vasodilation, in a pressure myograph. Flow-induced vasodilation was unaffected at a young age, but was significantly reduced in aging IUGR compared with aging controls ( P < 0.05). Underlying vasodilator mechanisms were altered such that nitric oxide-mediated vasodilation was abolished in both young adult and aging IUGR males and females and in aging control females ( P > 0.05). Endothelium-derived hyperpolarizing factor-mediated vasodilation was maintained in all groups ( P < 0.01). A change in the mechanisms of vasodilation occurring at an earlier age in IUGR offspring may predispose them to develop cardiovascular diseases as an aging adult.

Increased myogenic tone in 7-month-old adult male but not female offspring from rat dams exposed to hypoxia during pregnancy

2005 ◽  
Vol 289 (2) ◽  
pp. H674-H682 ◽  
Author(s):  
D. G. Hemmings ◽  
S. J. Williams ◽  
S. T. Davidge
Keyword(s):  
Vascular Function ◽  
Vascular Dysfunction ◽  
Female Offspring ◽  
Growth Restriction ◽  
Mesenteric Arteries ◽  
Adult Offspring ◽  
Dependent Manner ◽  
Maternal Undernutrition ◽  
Myogenic Responses ◽  
Prostaglandin H

Intrauterine growth restriction (IUGR) increases the risk of cardiovascular disease later in life. Vascular dysfunction occurs in adult offspring from animal models of IUGR including maternal undernutrition, but the influence of reduced fetal oxygen supply on adult vascular function is unclear. Myogenic responses, essential for vascular tone regulation, have not been evaluated in these offspring. We hypothesized that 7-mo-old offspring from hypoxic (12% O2; H) or nutrient-restricted (40% of control; NR) rat dams would show greater myogenic responses than their 4-mo-old littermates or control (C) offspring through impaired modulation by vasodilators. Growth restriction occurred in male H ( P < 0.01), male NR ( P < 0.01), and female NR ( P < 0.02), but not female H, offspring. Myogenic responses in mesenteric arteries from males but not females were increased at 7 mo in H ( P < 0.01) and NR ( P < 0.05) vs. C offspring. There was less modulation of myogenic responses after inhibition of nitric oxide synthase ( P < 0.05), prostaglandin H synthase ( P < 0.005), or both enzymes ( P < 0.001) in arteries from 7-mo male H vs. C offspring. Thus reduced vasodilator modulation may explain elevated myogenic responses in 7-mo male H offspring. In contrast, there was increased modulation of myogenic responses in arteries from 7-mo female H vs. C or NR offspring after inhibition of both enzymes ( P < 0.05). Thus increased vasodilator modulation may maintain myogenic responses in female H offspring at control levels. In summary, vascular responses in adult offspring from adverse intrauterine environments are impaired in a gender-specific, age-dependent, and maternal insult-dependent manner, with males more profoundly affected.

Mechanisms of endothelium-dependent vasodilation in male and female, young and aged offspring born growth restricted

2010 ◽  
Vol 298 (4) ◽  
pp. R930-R938 ◽  
Author(s):  
J. S. Morton ◽  
C. F. Rueda-Clausen ◽  
S. T. Davidge
Keyword(s):  
Gap Junctions ◽  
Vascular Function ◽  
Adult Life ◽  
In Utero ◽  
Mesenteric Arteries ◽  
Compensatory Mechanism ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Male And Female ◽  
The Impact

Numerous epidemiological studies have shown that cardiovascular dysfunction in adult life may be programmed by compromised growth in utero. Aging is a risk factor for vascular endothelial-dependent dysfunction. After birth, the impact of intrauterine growth restriction (IUGR) on normal aging mechanisms of vascular dysfunction is not known. We hypothesized that IUGR would cause changes in vascular function that would affect the mechanisms of endothelium-dependent vasodilation later in life in an age- or sex-dependent manner. To create an IUGR model, pregnant Sprague-Dawley rats were placed in a hypoxic (12% O2) or control (room air, 21% O2) environment from days 15 to 21 of the pregnancy, and both male and female offspring were investigated at 4 or 12 mo of age. Endothelial function was assessed in small mesenteric arteries using methacholine (MCh)-induced vasodilation in a wire myograph system. The involvement of nitric oxide (NO), prostaglandins, and endothelium-derived hyperpolarizing factor (EDHF) was assessed using the inhibitors Nω-nitro-l-arginine methyl ester hydrochloride, meclofenamate, or a combination of apamin and TRAM-34 (SKCa and IKCa blockers), respectively. EDHF-induced vasodilation was further investigated by using inhibitors of P450 epoxygenases [ N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide] and gap junctions (18α-glycyrrhetinic acid). NO-mediated vasodilation was significantly reduced in aged controls and both young and aged IUGR females. EDHF-mediated vasodilation was maintained in all groups; however, an additional involvement of gap junctions was found in females exposed to hypoxia in utero, which may represent a compensatory mechanism. A change in the mechanisms of vasodilation occurring at an earlier age in IUGR offspring may predispose them to adult cardiovascular diseases.

scholarly journals Paternal deficiency of complement component C1q leads to a preeclampsia-like pregnancy in wild-type female mice and vascular adaptations postpartum

2020 ◽  
Vol 318 (6) ◽  
pp. R1047-R1057
Author(s):  
Elizabeth F. Sutton ◽  
Mary Gemmel ◽  
Judith Brands ◽  
Marcia J. Gallaher ◽  
Robert W. Powers
Keyword(s):  
Vascular Function ◽  
Ex Vivo ◽  
Vascular Dysfunction ◽  
Late Gestation ◽  
Mesenteric Arteries ◽  
Wild Type ◽  
Specific Syndrome ◽  
Increased Risk ◽  
Pregnancy And Postpartum ◽  
Wild Type Female

Preeclampsia is a spontaneously occurring, pregnancy-specific syndrome that is clinically diagnosed by new onset hypertension and proteinuria. Epidemiological evidence describes an association between a history of preeclampsia and increased risk for cardiovascular disease in later life; however, the mechanism(s) driving this relationship are unclear. Our study aims to leverage a novel preeclampsia-like mouse model, the C1q−/− model, to help elucidate the acute and persistent vascular changes during and following a preeclampsia-like pregnancy. Female C57BL/6J mice were mated to C1q−/− male mice to model a preeclampsia-like pregnancy (“PE-like”), and the maternal cardiovascular phenotype (blood pressure, renal function, systemic glycocalyx, and ex vivo vascular function) was assessed in late pregnancy and postpartum at 6 and 10 mo of age. Uncomplicated, normotensive pregnancies (female C57BL/6J bred to male C57BL/6J mice) served as age-matched controls. In pregnancy, PE-like dams exhibited increased systolic and diastolic pressure during mid- and late gestation, renal dysfunction, fetal growth restriction, and reduced placental efficiency. Ex vivo wire myography studies of mesenteric arteries revealed severe pregnancy-specific endothelial-dependent and -independent vascular dysfunction. At 3 and 7 mo postpartum (6 and 10 mo old, respectively), hypertension resolved in PE-like dams, whereas mild vascular dysfunction persisted at 3 mo postpartum. In conclusion, the female C57BL/6J-by-male C57BL/6J C1q−/− model recapitulates many aspects of the human preeclampsia syndrome in a low-risk, wild-type female mouse. The pregnancy-specific phenotype results in systemic maternal endothelial-dependent and -independent vascular dysfunction that persists postpartum.

Abstract 189: Toll-like Receptor 2 Blockade Decreases Contractility in Angiotensin II-induced Hypertensive Rat Resistance Arteries

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Trevor Hardigan ◽  
Maria-Alicia Sepulveda ◽  
Kenia Pedrosa Nunes ◽  
R. Clinton Webb
Keyword(s):  
Angiotensin Ii ◽  
Vascular Dysfunction ◽  
Renin Angiotensin System ◽  
Mesenteric Arteries ◽  
Sodium Balance ◽  
Sprague Dawley ◽  
Resistance Arteries ◽  
Response Curves ◽  
Tlr2 Expression ◽  
The Impact

Toll-like receptors (TLRs) are pattern recognition receptors of the innate immune system that recognize endogenous damage-associated molecular patterns (DAMPS). TLR2 plays a role in cardiovascular diseases such as atherosclerosis and heart failure, but its role in hypertension is unknown. Angiotensin II (ANG), the effector molecule of the renin-angiotensin system, has been shown to cause an immune response leading to an inflammatory profile, in addition to its effects on vascular tone and sodium balance. We hypothesized that signaling through TLR2 in ANG-induced hypertension contributes to an increase in resistance artery contractility and vascular dysfunction. Sprague-Dawley rats were implanted with osmotic mini-pumps dispensing ANG (60 mg/day) for a 28 day period. Systolic blood pressure (measured directly via femoral canulation to confirm the ANG rats as a model of hypertension) was significantly increased in the ANG-treated rats (170 ±4.79 mmHg) vs. control (97 ±6.9 mmHg (p<0.05)). Concentration response curves to norepinephrine (NE; 10-9-10-4 M) were performed in second and third order mesenteric arteries from control and angiotensin-treated rats. Vessels were pre-incubated with and without antibody to TLR2 (1μg) for 35 minutes prior to the concentration-response curves to determine the impact of TLR2 blockade. The EMax (force of contraction as % of maximum KCl response) of the ANG vessels treated with anti-TLR2 was significantly lower than that of the ANG vessels alone (EMax: 129.2±10.69% vs 183.8±16.73%, respectively), and comparable to control-vessel levels (EMax in control vessels: 135.1±4.360%, p<0.05). Additionally, we sought to determine protein levels of TLR2 and downstream signaling protein MyD88 in the mesenteric arteries. In the arteries from the ANG treated animals, TLR2 expression was significantly increased 2.95±0.20 fold above control, and MyD88 expression was increased 1.35±0.06 fold above control (p<0.05). This suggests that TLR2 signaling leads to augmented contractility and is associated with the vascular dysfunction observed in hypertension.

Abstract P264: Endothelial-specific Interference With PPARγ Activity in Offspring Born From AVP-induced Preeclamptic Pregnancies Has Cardio-renal and Metabolic Consequences

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Anand R Nair ◽  
Masashi Mukohda ◽  
Larry N Agbor ◽  
Ko-Ting Lu ◽  
Jing Wu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Female Offspring ◽  
Reduce Blood Pressure ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Hypertensive Disorder ◽  
Peroxisome Proliferator Activated Receptor ◽  
The Impact

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor known to regulate metabolic and vascular function. Mutations in PPARγ result in hypertension, and synthetic agonists of PPARγ reduce blood pressure. Previously we found that mice expressing dominant-negative (DN) PPARγ driven by an endothelium-specific promoter (E-DN) exhibit vascular dysfunction. Preeclampsia (PE) is a hypertensive disorder of pregnancy which carries cardiovascular and metabolic risk to offspring. PE is associated with vascular dysfunction, and we therefore hypothesized a role for endothelial PPARγ in the pathogenesis of PE and its sequelae. C57BL/6J dams were bred with E-DN sires, and symptoms of PE were induced by the infusion of vasopressin (AVP, 24 ng/hr sc) throughout gestation. We assessed phenotypes of PE first in pregnant dams, and then in offspring as adults. Compared to saline infusion (SAL), AVP elevated maternal blood pressure (SBP: 116±3 vs 107±3, p<0.05) at gestational day (GD) 14-15 and urine protein (70±6 vs 27±4 mg/mL, p<0.05) at GD17. Offspring from these pregnancies were phenotyped in adulthood to assess cardiovascular and metabolic function. Data were stratified to sex, genotype, and maternal exposure to AVP vs SAL. Systolic blood pressure in adult male and female offspring born to AVP-infused pregnancies was similar to mice born to SAL pregnancies. At 20 weeks of age, vasorelaxation responses to acetylcholine were not different in offspring exposed to PE compared to mice born from SAL pregnancies. However, urinary protein levels were significantly elevated in both male (58±13 vs 32±5 mg/ml, p<0.05) and female (38±3 vs 25±2 mg/ml, p<0.05) adult E-DN born to PE pregnancies compared to E-DN controls born from SAL pregnancies. Male E-DN offspring exposed to PE showed significantly increased gain in body weight over time compared to male NT exposed to PE (ΔBW: 20±8 vs 14±2 g). These data highlight the impact of in utero exposure to elevated AVP upon cardiovascular function in the mother, and the adverse renal and metabolic consequences of PE upon offspring. Moreover, our data suggests that interference with endothelial PPARγ in pups born from PE pregnancies increases the risk for renal and metabolic dysfunction.

Abstract WMP109: Activation of the Brain Renin-Angiotensin System (RAS) Causes Selective Cerebrovascular Dysfunction

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Travice M De Silva ◽  
Justin Grobe ◽  
Frank M Faraci
Keyword(s):  
Vascular Function ◽  
Vascular Dysfunction ◽  
Tap Water ◽  
Cerebral Arteries ◽  
Rho Kinase ◽  
Renin Angiotensin System ◽  
Mesenteric Arteries ◽  
The Impact ◽  
The Brain

Hypertension is a leading risk factor for cerebrovascular disease. Although many changes during hypertension may be mediated by the RAS, most hypertensive patients have normal or reduced levels of circulating renin, suggesting that local tissue RAS play a key role. Surprisingly, little is known regarding the impact of the brain RAS on the cerebral vasculature. We tested the hypothesis that activation of the central RAS using deoxycorticosterone (DOCA)-salt (which simultaneously suppresses the peripheral RAS) alters vascular function. Male C57Bl/6 mice treated with DOCA were given both tap water and water with 0.9% salt for 3 weeks, followed by measurements of vessel reactivity. Mean arterial pressure was elevated modestly after DOCA-salt (79±2 vs 95±3 mmHg; P<0.01). In DOCA-salt treated mice, endothelium-dependent dilation of isolated middle cerebral arteries was almost abolished compared to shams, whereas dilation in mesenteric arteries was normal. This striking effect in brain extended to small parenchymal arterioles. Endothelium-independent vasodilation was similar in all groups. Analysis of mRNA revealed that expression of renal renin was markedly reduced by DOCA-salt while expression of RAS components (eg, AGT, ACE) were increased in both brain and cerebral arteries. In NZ44 reporter mice that express GFP driven by the angiotensin II type 1A receptor (AT1AR) promoter, DOCA-salt significantly increased AT1R-GFP protein expression in cerebral arteries. In cerebral arterioles in vivo, local inhibition of AT1R, mineralocorticoid receptors (MR), or Rho kinase (including ROCK2) reversed endothelial dysfunction in DOCA-salt treated mice. These findings suggest for the first time that activation of the brain and the cerebrovascular RAS profoundly, but selectively, impairs vascular function in brain. Our findings identify AT1R, MR and Rho kinase as key contributors to vascular dysfunction in brain in a clinically relevant model of hypertension.

scholarly journals Differential Deleterious Impact of Highly Saturated Versus Monounsaturated Fat Intake on Vascular Function, Structure, and Mechanics in Mice

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 1003
Author(s):  
Elena Vega-Martín ◽  
Marta Gil-Ortega ◽  
Raquel González-Blázquez ◽  
Sara Benedito ◽  
Jesús Fernández-Felipe ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Arterial Stiffness ◽  
Thoracic Aorta ◽  
Vascular Function ◽  
Saturated Fatty Acids ◽  
Vascular Wall ◽  
Monounsaturated Fatty Acids ◽  
Mesenteric Arteries ◽  
Monounsaturated Fat ◽  
The Impact

Vegetable oils such as palm oil (enriched in saturated fatty acids, SFA) and high-oleic-acid sunflower oil (HOSO, containing mainly monounsaturated fatty acids, MUFA) have emerged as the most common replacements for trans-fats in the food industry. The aim of this study is to analyze the impact of SFA and MUFA-enriched high-fat (HF) diets on endothelial function, vascular remodeling, and arterial stiffness compared to commercial HF diets. Five-week-old male C57BL6J mice were fed a standard (SD), a HF diet enriched with SFA (saturated oil-enriched Food, SOLF), a HF diet enriched with MUFA (unsaturated oil-enriched Food, UOLF), or a commercial HF diet for 8 weeks. Vascular function was analyzed in the thoracic aorta. Structural and mechanical parameters were assessed in mesenteric arteries by pressure myography. SOLF, UOLF, and HF diet reduced contractile responses to phenylephrine and induced endothelial dysfunction in the thoracic aorta. A significant increase in the β-index, and thus in arterial stiffness, was also detected in mesenteric arteries from the three HF groups, due to enhanced deposition of collagen in the vascular wall. SOLF also induced hypotrophic inward remodeling. In conclusion, these data demonstrate a deleterious effect of HF feeding on obesity-related vascular alterations that is exacerbated by SFA.

scholarly journals Programming of growth, insulin resistance and vascular dysfunction in offspring of late gestation diabetic rats

2009 ◽  
Vol 117 (3) ◽  
pp. 129-138 ◽  
Author(s):  
Emily M. Segar ◽  
Andrew W. Norris ◽  
Jian-Rong Yao ◽  
Shanming Hu ◽  
Stacia L. Koppenhafer ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Diabetic Rats ◽  
Late Gestation ◽  
Group Differences ◽  
Pregnant Rats ◽  
Increased Risk ◽  
Specific Insulin ◽  
Diabetic Mothers

ODM (offspring of diabetic mothers) have an increased risk of developing metabolic and cardiovascular dysfunction; however, few studies have focused on the susceptibility to disease in offspring of mothers developing diabetes during pregnancy. We developed an animal model of late gestation diabetic pregnancy and characterized metabolic and vascular function in the offspring. Diabetes was induced by streptozotocin (50 mg/kg of body weight, intraperitoneally) in pregnant rats on gestational day 13 and was partially controlled by twice-daily injections of insulin. At 2 months of age, ODM had slightly better glucose tolerance than controls (P<0.05); however, by 6 months of age this trend had reversed. A euglycaemic–hyperinsulinamic clamp revealed insulin resistance in male ODM (P<0.05). In 6–8-month-old female ODM, aortas had significantly enhanced contractility in response to KCl, ET-1 (endothelin-1) and NA (noradrenaline). No differences in responses to ET-1 and NA were apparent with co-administration of L-NNA (NG-nitro-L-arginine). Relaxation in response to ACh (acetylcholine), but not SNP (sodium nitroprusside), was significantly impaired in female ODM. In contrast, males had no between-group differences in response to vasoconstrictors, whereas relaxation to SNP and ACh was greater in ODM compared with control animals. Thus the development of diabetes during pregnancy programmes gender-specific insulin resistance and vascular dysfunction in adult offspring.

Arterial stiffness and carotid distensibility following acute formaldehyde exposure in female adults

2021 ◽  
pp. 074823372110316
Author(s):  
Nina L Stute ◽  
Jonathon L Stickford ◽  
Marc A Augenreich ◽  
Kyle C Kimball ◽  
Janet M Cope ◽  
...  
Keyword(s):  
Arterial Stiffness ◽  
Vascular Function ◽  
Intima Media Thickness ◽  
Human Cadaver ◽  
Media Thickness ◽  
Carotid Stiffness ◽  
Short Term Exposure ◽  
Increased Risk ◽  
Carotid Distensibility ◽  
The Impact

Formaldehyde (FA) is a ubiquitous organic preservative used in several industries and represents an occupational health hazard. Short-term exposure to FA can increase oxidative stress and cause a decrease in conduit vessel function. These decrements in vascular function may extend to the arterial architecture, predisposing individuals to increased risk of cardiovascular disease. The purpose of this study was to investigate the impact of an acute 90-minute FA exposure period (259 ± 95 ppb) on indices of arterial architecture. Arterial stiffness and carotid distensibility as determined by central pressures, augmentation index (AIx), and carotid-femoral pulse wave velocity (cfPWV) ( n=13F, 24 ± 1 year) as well as carotid stiffness and intima media thickness (IMT) ( n = 9F, 23 ± 1 year) were assessed prior to (Pre-FA) and immediately following (Post-FA) exposure to FA in human cadaver dissection laboratories. Central pressures and cfPWV (Pre-FA: 5.2 ± 0.8 m.s−1, Post-FA: 5.2 ± 1.1 m s−1) were unchanged by acute FA exposure ( p > 0.05). Carotid stiffness parameters and distension were unchanged by acute FA exposure ( p > 0.05), although distensibility (Pre-FA: 33.9 ± 10.5[10–3*kPa−1], Post-FA: 25.9 ± 5.5[10–3*kPa-1], p < 0.05), and IMT (Pre-FA: 0.42 ± 0.05 mm, Post-FA: 0.51 ± 0.11 mm, p < 0.05) decreased and increased, respectively. Individual Pre- to Post-FA changes in these markers of arterial architecture did not correlate with levels of FA exposure ([FA]: 20–473 ppb) ( p > 0.05). Our group previously found vascular function decrements following acute FA exposure in human cadaver laboratories; here we found that carotid distensibility and intima media thickness are altered following FA exposure.

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

Hypertension ◽  
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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