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.

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.

Gender differences in myogenic tone in superoxide dismutase knockout mouse: animal model of oxidative stress

2004 ◽  
Vol 287 (1) ◽  
pp. H40-H45 ◽  
Author(s):  
Sukrutha Veerareddy ◽  
Christy-Lynn M. Cooke ◽  
Philip N. Baker ◽  
Sandra T. Davidge
Keyword(s):  
Oxidative Stress ◽  
Vascular Function ◽  
Vascular Tone ◽  
Vascular Dysfunction ◽  
Mesenteric Arteries ◽  
Myogenic Tone ◽  
Intracellular Enzyme ◽  
Male And Female ◽  
Prostaglandin H ◽  
Myogenic Regulation

Oxidative stress mediated by prooxidants has been implicated in the pathogenesis of vascular disorders. However, the effect of prooxidants on myogenic regulation of vascular function and the differential influence of gender is not known. SOD, an intracellular enzyme, restricts excess prooxidant levels and may limit vascular dysfunction. We therefore tested the effects of Cu,Zn SOD deficiency on vascular tone in both male and female SOD knockout (SOD−/−) mice. We hypothesized that myogenic tone would be enhanced in SOD−/− mice by excess prooxidants compared with wild-type control mice. Indeed, resistance-sized mesenteric arteries from SOD−/− mice exhibited enhanced myogenic tone compared with control mice. Myogenic tone was lower in female than male control mice. Interestingly, this gender effect was absent in SOD−/− mice, such that myogenic tone of mesenteric arteries from females was equated to that of arteries from males. Furthermore, the pathways that modulate myogenic tone were diverse. In both male and female control mice, inhibition of prostaglandin H synthase (PGHS) and nitric oxide synthase (NOS) pathways enhanced myogenic tone. In female SOD−/− mice, inhibition of PGHS and NOS pathways enhanced myogenic tone to a greater extent compared with control mice. Conversely, in male SOD−/− mice, NOS and PGHS inhibition did not alter tone and only inhibition of gap junctions enhanced myogenic tone. In conclusion, this study revealed enhanced myogenic tone in SOD−/− mice compared with control mice. Furthermore, Cu,Zn SOD deficiency particularly enhanced myogenic tone in female mice such that their vascular tone attained the level of male SOD−/− mice, possibly mediated by prooxidants.

Abstract 03: Ablation Of Endothelial Dysfunction Improves Blood Pressure And Fetal Growth Restriction In A Mouse Model Of Preeclampsia-like Hyperleptinemia

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Jessica L Faulkner ◽  
Derrian Wright ◽  
Simone Kennard ◽  
Galina Antonova ◽  
Iris Z Jaffe ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Fold Change ◽  
Growth Restriction ◽  
Mesenteric Arteries ◽  
Pregnant Mice ◽  
Placental Efficiency

Placental ischemia, an initiating event of preeclampsia (PE), increases plasma leptin levels. We recently developed a model of midgestation (gestation day (GD)11-18) leptin infusion mimicking the midgestation rise in leptin levels of PE patients. Our previous work demonstrates that deletion of endothelial mineralocorticoid receptors (ECMR) improves markers of vascular dysfunction in leptin-infused female mice. We hypothesized vascular function improvement with ECMR deletion ablates hypertension and fetal growth restriction in pregnant leptin-infused mice. Pregnant ECMR +/+ (WT) and ECMR -/- (KO) mice were infused with vehicle or leptin by osmotic pump (lep, 0.9mg/kg/day, s.c.) on GD11-18 while implanted with radiotelemeters for conscious blood pressure (BP) measurement and wire myography of thoracic aorta and 2 nd order mesenteric arteries at GD18 (*=P<0.05). Leptin infusion did not decrease maternal weight in any groups. Leptin decreased pup weight (0.86±0.04g WT vs 0.52±0.11 WT+lep*) and placental efficiency (pup/placenta ratio) (9.7±0.7 WT vs 7.9±0.6 WT+lep*) in WT pregnant mice. ECMR deletion prevented leptin-mediated decreases in pup weight (0.91±0.06g KO vs 1.0±0.07 KO+lep) and placental efficiency (9.6±0.5 KO vs 9.4±1.2 KO+lep). Mean arterial pressure (BP) increased in leptin-infused WT (102±3mmHg WT vs 120±12 WT+lep*), but not KO (107±2 KO vs 106±8 KO+lep), mice from GD11-18. Leptin infusion reduced acetylcholine-mediated relaxation in both aorta and mesenteric arteries of WT* and constriction to KCl in mesenteric arteries in WT*, but not KO, pregnant mice (2-way ANOVA, repeated measures). Leptin increased plasma endothelin-1 (ET-1, 1.1±0.3 pg/ml WT vs 4.4±1.8 WT+lep*), placental mRNA expression of prepro-ET-1 (1.9±0.3-fold change from WT*) and ET-1 converting enzyme-1 (1.6±0.3-fold change from WT*) in pregnant WT mice. Leptin infusion also increased adrenal aldosterone-synthase protein (1.4±0.4 WT ratio/β actin vs 3.2±0.3 WT+lep*) and angiotensin II type 1 receptor b (3.5±0.8-fold change from WT*) mRNA in pregnant mice. Collectively, these data indicate that leptin infusion induces hypertension and fetal growth restriction in pregnant mice due to vascular dysfunction and increased ECMR activation in pregnant mice.

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.

Estrogen replacement reduces PGHS-2-dependent vasoconstriction in the aged rat

2002 ◽  
Vol 283 (3) ◽  
pp. H893-H898 ◽  
Author(s):  
Stephen J. Armstrong ◽  
Yunlong Zhang ◽  
Ken G. Stewart ◽  
Sandra T. Davidge
Keyword(s):  
Nitric Oxide ◽  
Vascular Dysfunction ◽  
Mesenteric Arteries ◽  
Estrogen Replacement ◽  
Aged Rat ◽  
Arterial Relaxation ◽  
Prostaglandin H ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Endothelium Dependent Relaxation

The reduction in estrogen in postmenopausal women contributes to an increase in vascular dysfunction. Models of aging have shown that this is due, in part, to increased prostaglandin H synthase (PGHS)-dependent vasoconstriction. We showed previously that inducible PGHS-2-dependent vasoconstriction is increased with aging. In the present study, we hypothesized that estrogen suppresses PGHS-2-dependent constriction in the aged rat. Isolated mesenteric arteries from placebo- or estrogen-treated, ovariectomized aged (24 mo) Fisher rats were assessed for endothelium-dependent relaxation in the absence or presence of PGHS inhibitors. PGHS inhibition (meclofenamate, 1 μmol/l) enhanced methacholine-induced relaxation only in the placebo group. Specific PGHS-2 inhibition (NS-398, 10 μmol/l) increased arterial relaxation to a greater extent than PGHS-1 inhibition (valeryl salicylate, 3 mmol/l). Estrogen prevented the PGHS-dependent constrictor effect but did not enhance nitric oxide-dependent relaxation in this model. PGHS-1 and endothelial nitric oxide synthase were not altered by estrogen, whereas PGHS-2 expression was decreased in the estrogen-replaced rats ( P < 0.05). In summary, estrogen replacement improved vasodilation in aged rats by decreasing PGHS-dependent constriction.

scholarly journals Accelerated age-related decline in renal and vascular function in female rats following early-life growth restriction

2015 ◽  
Vol 309 (9) ◽  
pp. R1153-R1161 ◽  
Author(s):  
M. Jane Black ◽  
Kyungjoon Lim ◽  
Monika A. Zimanyi ◽  
Amanda K. Sampson ◽  
Kristen J. Bubb ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Early Life ◽  
Structural Damage ◽  
Female Offspring ◽  
Growth Restriction ◽  
Mesenteric Arteries ◽  
Protein Diet ◽  
Female Rats ◽  
Age Related ◽  
Increased Risk

Many studies report sexual dimorphism in the fetal programming of adult disease. We hypothesized that there would be differences in the age-related decline in renal function between male and female intrauterine growth-restricted rats. Early-life growth restriction was induced in rat offspring by administering a low-protein diet (LPD; 8.7% casein) to dams during pregnancy and lactation. Control dams were fed a normal-protein diet (NPD; 20% casein). Mean arterial pressure (MAP) and renal structure and function were assessed in 32- and 100-wk-old offspring. Mesenteric artery function was examined at 100 wk using myography. At 3 days of age, body weight was ∼24% lower ( P < 0.0001) in LPD offspring; this difference was still apparent at 32 wk but not at 100 wk of age. MAP was not different between the male NPD and LPD groups at either age. However, MAP was greater in LPD females compared with NPD females at 100 wk of age (∼10 mmHg; P < 0.001). Glomerular filtration rate declined with age in the NPD male, LPD male and LPD female offspring (∼45%, all P < 0.05), but not in NPD female offspring. Mesenteric arteries in the aged LPD females had reduced sensitivity to nitric oxide donors compared with their NPD counterparts, suggesting that vascular dysfunction may contribute to the increased risk of disease in aged females. In conclusion, females growth-restricted in early life were no longer protected from an age-related decline in renal and arterial function, and this was associated with increased arterial pressure without evidence of renal structural damage.

Abstract 44: VEGF Inhibitor-induced Vascular Dysfunction Is Ameliorated By PARP/TRPM2 Inhibition

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Karla B Neves ◽  
Rheure Alves-lopes ◽  
Ninian Lang ◽  
Augusto C Montezano ◽  
Rhian M Touyz
Keyword(s):  
Cancer Treatment ◽  
Vascular Injury ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Parp Inhibitor ◽  
Mesenteric Arteries ◽  
Cancer Drug ◽  
Vegf Inhibitors ◽  
Vegf Inhibitor ◽  
Trpm2 Channel

Hypertension is a common unwanted effect of VEGF inhibitors (VEGFi), which are used as anti-angiogenic drugs in cancer treatment. Clinical observations suggest that the combination of VEGFi with another anti-cancer drug, olaparib (PARP inhibitor [PARPi]), may attenuate the development of hypertension. However putative vascular mechanisms are unknown. PARP plays a major role in the activation of TRPM2, a redox-sensitive Ca 2+ channel, which is associated with hypertension-induced vascular dysfunction. We hypothesized that PARPi attenuates VEGFi-induced vascular injury through TRPM2/Ca 2+ -dependent pathways. Human vascular smooth muscle cells (hVSMC), human aortic endothelial cells (HAEC), and mouse mesenteric arteries were studied. Cells/arteries were exposed to axitinib (VEGFi) alone (3μM) or in combination with olaparib (1μM). Wire myography was used to assess vascular function. Axitinib reduced ACh-induced vasodilation (% relaxation: 70.5 [Ct] vs. 34.8 [Axi]), an effect blocked by olaparib. U46619- and ET-1-induced vasoconstriction were increased by axitinib (% KCl- U4 : 101.2 [Ct] vs. 141.4 [Axi]; ET-1 : 122.6 [Ct] vs. 152.5 [Axi]), an effect not observed with axitinib plus olaparib. TRPM2 channel blocker (8-Br-cADPR; 1μM) attenuated the hypercontractile effects and endothelial dysfunction induced by axitinib. Axitinib increased ROS production in hVSMC (RUL: 0.8±0.2 [Ct] vs. 1.1±0.09 [Axi]) and HAEC (0.7±0.4 [Ct] vs. 1.2±0.1 [Axi]), stimulated phosphorylation of the inhibitory site of eNOS (a.u.: 0.99±0.35 [Ct] vs. 1.35±0.10 [Axi]) and induced exaggerated Ca 2+ influx (AUC: 17541±4708 [Ct] vs. 22249±1438 [Axi]) in hVSMC. These effects were blocked by olaparib and 8-Br-cADPR. Axitinib also induced phosphorylation of MLC20 in hVSMC (a.u.: 0.028±0.02 [Ct] vs. 0.04±0.01 [Axi]) and aorta (a.u.: 0.3±0.01 [Ct] vs. 0.5±0.001 [Axi]). Our data indicate that PARP/TRPM2 inhibition attenuates axitinib-mediated vascular dysfunction and normalizes impaired hVSMC and HAEC signalling induced by VEGFi. We define a putative vasoprotective effect of olaparib that may ameliorate vascular injury and hypertension induced by VEGFi in cancer treatment.

scholarly journals eNOS knockout mouse as a model of fetal growth restriction with an impaired uterine artery function and placental transport phenotype

2012 ◽  
Vol 303 (1) ◽  
pp. R86-R93 ◽  
Author(s):  
Laura C. Kusinski ◽  
Joanna L. Stanley ◽  
Mark R. Dilworth ◽  
Cassandra J. Hirt ◽  
Irene J. Andersson ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Vascular Function ◽  
Uterine Artery ◽  
Nutrient Transport ◽  
Growth Restriction ◽  
Growth Potential ◽  
Abdominal Circumference ◽  
Maternal Undernutrition ◽  
Endothelial Nitric Oxide

Fetal growth restriction (FGR) is the inability of a fetus to reach its genetically predetermined growth potential. In the absence of a genetic anomaly or maternal undernutrition, FGR is attributable to “placental insufficiency”: inappropriate maternal/fetal blood flow, reduced nutrient transport or morphological abnormalities of the placenta (e.g., altered barrier thickness). It is not known whether these diverse factors act singly, or in combination, having additive effects that may lead to greater FGR severity. We suggest that multiplicity of such dysfunction might underlie the diverse FGR phenotypes seen in humans. Pregnant endothelial nitric oxide synthase knockout (eNOS−/−) dams exhibit dysregulated vascular adaptations to pregnancy, and eNOS−/− fetuses of such dams display FGR. We investigated the hypothesis that both altered vascular function and placental nutrient transport contribute to the FGR phenotype. eNOS−/− dams were hypertensive prior to and during pregnancy and at embryonic day (E) 18.5 were proteinuric. Isolated uterine artery constriction was significantly increased, and endothelium-dependent relaxation significantly reduced, compared with wild-type (WT) mice. eNOS−/− fetal weight and abdominal circumference were significantly reduced compared with WT. Unidirectional maternofetal 14C-methylaminoisobutyric acid (MeAIB) clearance and sodium-dependent 14C-MeAIB uptake into mouse placental vesicles were both significantly lower in eNOS−/− fetuses, indicating diminished placental nutrient transport. eNOS−/− mouse placentas demonstrated increased hypoxia at E17.5, with elevated superoxide compared with WT. We propose that aberrant uterine artery reactivity in eNOS−/− mice promotes placental hypoxia with free radical formation, reducing placental nutrient transport capacity and fetal growth. We further postulate that this mouse model demonstrates “uteroplacental hypoxia,” providing a new framework for understanding the etiology of FGR in human pregnancy.

scholarly journals Raised saturated-fat intake worsens vascular function in virgin and pregnant offspring of streptozotocin-diabetic rats

2000 ◽  
Vol 84 (3) ◽  
pp. 285-296 ◽  
Author(s):  
Kathleen Holemans ◽  
Robert Gerber ◽  
Ivan O'Brien-Coker ◽  
Anthony Mallet ◽  
Rieta Van Bree ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Saturated Fat ◽  
Diabetic Rats ◽  
Mesenteric Arteries ◽  
Fat Intake ◽  
Pregnant Rats ◽  
Insulin Resistant ◽  
Saturated Fat Intake

Adult offspring of severely diabetic pregnant rats are insulin resistant and display cardiovascular dysfunction. When pregnant they develop mild hyperglycaemia. Diets high in saturated fat have been implicated in the development of cardiovascular disease and vascular dysfunction. In the present study we have determined vascular function in small mesenteric arteries from offspring of normal (OC) and diabetic (OD) rats fed standard chow and offspring of diabetic rats fed a diet high in saturated fats (OD-HF) from weaning to adulthood, and throughout their subsequent pregnancies. OD rats displayed an increased sensitivity to noradrenaline (P < 0·05) and impaired sensitivity to the endothelium-dependent vasodilator, acetylcholine. The component of acetylcholine-induced relaxation attributable to endothelium-derived hyperpolarizing factor was reduced in OD-HF rats. Pregnant OD rats also demonstrated impaired maximum relaxation to acetylcholine (pregnant OD rats v. pregnant OC rats P < 0·05). In pregnant OD-HF rats noradrenaline sensitivity was enhanced and endothelium-dependent relaxation further reduced (pregnant OD-HF rats v. pregnant OC rats P < 0·001). The isoprostane, 8-epi-prostaglandin F2α, a marker of oxidative stress, was increased in pregnant OD rats (pregnant OD rats v. pregnant OC rats P < 0·001) and further increased in pregnant OD-HF rats (pregnant OD-HF rats v. pregnant OD rats P < 0·05). We conclude that a high-saturated-fat diet leads to deterioration in specific components of vascular function in OD rats. When pregnant, vascular function of OD-HF rats is further compromised. Pregnancy in the OD rats is associated with a striking increase in a marker of oxidative stress, which increases further if the saturated fat intake is raised.

Abstract P277: β-arrestin-2-mediated Vasodilatation In Mouse Mesenteric Arteries

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Victor M Pulgar ◽  
Krisztian Toth
Keyword(s):  
Vascular Function ◽  
Isometric Force ◽  
Mesenteric Arteries ◽  
Maximal Response ◽  
Lower Sensitivity ◽  
Dependent Manner ◽  
Resistance Arteries ◽  
Response Curves ◽  
Vascular Dilatation

As part of GPCRs-dependent signaling, β -arrestin-2 has been shown to stimulate eNOS activity and thus has the potential to modulate vascular function. We hypothesized that the absence of β -arrestin-2 would alter vascular dilatation and contraction in resistance arteries. We tested acetylcholine (ACh)-dependent relaxation and phenylephrine (PE)-dependent contraction in mouse mesenteric arteries isolated from 3-mo old male C57Bl6 (WT, n=5) and β -arrestin-2 KO ( βarr2 -/- , n=5) mice. Segments were mounted in a Wire Myograph (DMT) for determination of isometric force; vessels studied included intact, without endothelium, or pre-incubated with L-NAME (10 -4 M). Dose-response curves were performed for ACh (10 -10 -10 -4.5 M) and PE (10 -10 -10 -4.5 M). Data were acquired using a PowerLab (ADInstruments) system. Maximal response to ACh (ACh MAX ) was expressed as maximal relaxation after pre-constriction, maximal response to PE (PE MAX ) as % of contraction to 75mM KCl (%K MAX ), and sensitivity as pD 2 (-Log[EC 50 ]). Data were analyzed using Prism (GraphPad). After pre-constriction (PE, 3x10 -6 M), arteries from βarr2 -/- mice presented similar ACh MAX (79±6 vs. 82±6, p>0.05) and lower sensitivity to ACh compared to WT (6.66±0.2 vs. 7.12±0.1, p<0.05). The sensitivity of the contraction to PE was increased in βarr2 -/- arteries (6.4±0.2 vs. 6.04±0.1, p<0.05), with no changes in PE MAX . Differences in vasodilation and contraction were abolished in arteries without endothelium and in arteries pre-incubated with L-NAME. We conclude that the absence of β -arrestin-2 induces a pro-contractile phenotype in an endothelium- and nitric oxide-dependent manner in mouse resistance arteries.

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