scholarly journals C21 preserves endothelial function in the thoracic aorta from DIO mice: role for AT2, Mas and B2 receptors

2021 ◽  
Author(s):  
Raquel González-Blázquez ◽  
Martín Alcalá ◽  
María Fernández-Alfonso ◽  
Ulrike Muscha Steckelings ◽  
María Paz Lorenzo ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Signaling Pathways ◽  
Thoracic Aorta ◽  
Vascular Reactivity ◽  
Ang Ii ◽  
Diet Induced Obesity ◽  
Angiotensin Type 2 Receptor ◽  
No Release ◽  
Compound 21 ◽  
B2 Receptors

Compound 21 (C21), a selective agonist of angiotensin type 2 receptor (AT2R), induces vasodilation through NO release. Since AT2R seems to be overexpressed in obesity, we hypothesize that C21 prevents the development of obesity-related vascular alterations. The main goal of this study was to assess the effect of C21on thoracic aorta endothelial function in a model of diet-induced obesity and to elucidate the potential crosstalk between AT2R, MasR and/or B2R in this response. 5-week-old male C57BL6J mice were fed a standard (CHOW) or a high-fat diet (HF) for 6 weeks and treated daily with C21 (1mg/Kg p.o) or vehicle, generating four groups: CHOW-C, CHOW-C21, HF-C, HF-C21. Vascular reactivity experiments were performed in thoracic aorta rings. Human endothelial cells (EA.hy926) were used to elucidate the signaling pathways, both at receptor and intracellular levels.Arteries from HF mice exhibited increased contractions to Ang II than CHOW mice, effect that was prevented by C21. PD123177, A779 and HOE-140 (AT2R, Mas and B2R antagonists) significantly enhanced Ang II-induced contractions in CHOW but not in HF-C rings, suggesting a lack of functionality of those receptors in obesity. C21 prevented those alterations and favoured the formation of AT2R/MasR and MasR/B2R heterodimers. HF mice also exhibited impaired relaxations to acetylcholine due to a reduced NO availability. C21 preserved NO release through PKA/p-eNOS and AKT/p-eNOS signaling pathways. In conclusion, C21 favours the interaction between AT2R, MasR and B2R and prevents the development of obesity-induced endothelial dysfunction by stimulating NO release through PKA/p-eNOS and AKT/p-eNOS signaling pathways.

scholarly journals COMPOUND 21 IMPROVES VASCULAR FUNTION IN THE THORACIC AORTA FROM OBESE MICE: IMPLICATION OF AT2, MAS AND B2 RECEPTORS

2021 ◽  
Vol 39 (Supplement 1) ◽  
pp. e336-e337
Author(s):  
Raquel González-Blázquez ◽  
Marta Gil-Ortega ◽  
Martín Alcalá ◽  
Marta Viana ◽  
Thomas Unger ◽  
...  
Keyword(s):  
Thoracic Aorta ◽  
Obese Mice ◽  
Compound 21 ◽  
B2 Receptors

scholarly journals Vena cava presents endothelial dysfunction prior to thoracic aorta in heart failure: the pivotal role of nNOS uncoupling/ oxidative stress

2021 ◽  
Author(s):  
Patrizia Dardi ◽  
Laís Rossi Perazza ◽  
Gisele Kruger Couto ◽  
Gianne Paul Campos ◽  
Luciano dos Santos Aggum Capettini ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Thoracic Aorta ◽  
Vascular Reactivity ◽  
Vena Cava ◽  
Coronary Artery Occlusion ◽  
H2o2 Production ◽  
No Production

Arterial endothelial dysfunction has been extensively studied in heart failure (HF). However little is known about the adjustments shown by the venous system in this condition. Considering that inferior vena cava (VC) tone could influence cardiac performance and HF prognosis, the aim of the present study was to assess the VC and thoracic aorta (TA) endothelial function of HF-post-myocardial infarction (MI) rats, comparing both endothelial responses and signaling pathways developed. Vascular reactivity of TA and VC from HF post-MI and sham operated (SO) rats was assessed with a wire myograph, four weeks after coronary artery occlusion surgery. Nitric oxide (NO), H2O2 production and oxidative stress were evaluated in situ with fluorescent probes, whilst protein expression and dimer/monomer ratio was assessed by western blot. VC from HF rats presented endothelial dysfunction, while TA exhibited higher acetylcholine (ACh)-induced vasodilation when compared to vessels from SO rats. TA exhibited increased ACh-induced NO production due to a higher coupling of endothelial and neuronal NO synthases isoforms (eNOS, nNOS), and enhanced expression of antioxidant enzymes. These adjustments, however, were absent in VC of HF post-MI rats, which exhibited uncoupled nNOS, oxidative stress and higher H2O2 bioavailability. Altogether, this study suggests a differential regulation of endothelial function between VC and TA of HF post-MI rats, most likely due to nNOS uncoupling and compromised antioxidant defense.

scholarly journals Acute Effects of Triiodothyronine on Endothelial Function in Human Subjects

2007 ◽  
Vol 92 (1) ◽  
pp. 250-254 ◽  
Author(s):  
Raffaele Napoli ◽  
Vincenzo Guardasole ◽  
Valentina Angelini ◽  
Emanuela Zarra ◽  
Daniela Terracciano ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Dose Response ◽  
Vascular Reactivity ◽  
Controlled Trial ◽  
University Hospital ◽  
Acute Effects ◽  
Response Curves ◽  
Double Blind ◽  
Low T3 ◽  
Dose Response Curves

Abstract Context: Thyroid hormone regulates several cardiovascular functions, and low T3 levels are frequently associated with cardiovascular diseases. Whether T3 exerts any acute and direct effect on endothelial function in humans is unknown. Objective: Our objective was to clarify whether acute changes in serum T3 concentration affect endothelial function. Design, Setting, and Subjects: Ten healthy subjects (age, 24 ± 1 yr) participated in a double-blind, placebo-controlled trial at a university hospital. Interventions: T3 (or placebo) was infused for 7 h into the brachial artery to raise local T3 to levels observed in moderate hyperthyroidism. Vascular reactivity was tested by intraarterial infusion of vasoactive agents. Main Outcome Measures: We assessed changes in forearm blood flow (FBF) measured by plethysmography. Results: FBF response to the endothelium-dependent vasodilator acetylcholine was enhanced by T3 (P = 0.002 for the interaction between T3 and acetylcholine). The slopes of the dose-response curves were 0.41 ± 0.06 and 0.23 ± 0.04 ml/dl·min/μg in the T3 and placebo study, respectively (P = 0.03). T3 infusion had no effect on the FBF response to sodium nitroprusside. T3 potentiated the vasoconstrictor response to norepinephrine (P = 0.006 for the interaction). Also, the slopes of the dose-response curves were affected by T3 (1.95 ± 0.77 and 3.83 ± 0.35 ml/dl·min/mg in the placebo and T3 study, respectively; P < 0.05). The increase in basal FBF induced by T3 was inhibited by NG-monomethyl-l-arginine. Conclusions: T3 exerts direct and acute effects on the resistance vessels by enhancing endothelial function and norepinephrine-induced vasoconstriction. The data may help clarify the vascular impact of the low T3 syndrome and point to potential therapeutic strategies.

Evidence of preserved endothelial function and vascular plasticity with age

2006 ◽  
Vol 290 (3) ◽  
pp. H1271-H1277 ◽  
Author(s):  
D. Walter Wray ◽  
Abhimanyu Uberoi ◽  
Lesley Lawrenson ◽  
Russell S. Richardson
Keyword(s):  
Exercise Training ◽  
Endothelial Function ◽  
Vascular Reactivity ◽  
Knee Extensor ◽  
Handgrip Exercise ◽  
Age Related ◽  
Older Subjects ◽  
Small Muscle ◽  
Flow Mediated Vasodilation ◽  
Cuff Occlusion

We sought to identify the relationship between shear stimuli and flow-mediated vasodilation and to determine whether small muscle mass exercise training could provoke limb-specific improvements in endothelial function in older subjects. In five young (22 ± 1 yr old) and six old (71 ± 2 yr old) subjects, ultrasound Doppler measurements were taken in the arm (brachial artery) and leg (deep and superficial femoral arteries) after suprasystolic cuff occlusion with and without ischemic exercise to evaluate flow-mediated dilation (FMD) in both limbs. Older subjects were reevaluated after 6 wk of single-leg knee extensor exercise training. Before the training, a significant FMD was observed in the arm of young (3 ± 1%) but not old (1 ± 1%) subjects, whereas a significant leg FMD was observed in both groups (5 ± 1% old vs. 3 ± 1% young). However, arm vasodilation was similar between young and old when normalized for shear rate, and cuff occlusion with superimposed handgrip exercise provoked additional shear, which proportionately improved the FMD response in both groups. Exercise training significantly improved arm FMD (5 ± 1%), whereas leg FMD was unchanged. However, ischemic handgrip exercise did not provoke additional arm vasodilation after training, which may indicate an age-related limit to shear-induced vasodilation. Together, these data demonstrate that vascular reactivity is dependent on limb and degree of shear stimuli, challenging the convention of diminished endothelial function typically associated with age. Likewise, exercise training improved arm vasodilation, indicating some preservation of vascular plasticity with age.

Enhanced vasodilation to acetylcholine in athletes is associated with lower plasma cholesterol

1996 ◽  
Vol 270 (6) ◽  
pp. H2008-H2013 ◽  
Author(s):  
B. A. Kingwell ◽  
B. Tran ◽  
J. D. Cameron ◽  
G. L. Jennings ◽  
A. M. Dart
Keyword(s):  
Sodium Nitroprusside ◽  
Vascular Resistance ◽  
Repeated Measures ◽  
Vascular Reactivity ◽  
Plasma Cholesterol ◽  
Total Cholesterol Level ◽  
Venous Occlusion ◽  
Ang Ii ◽  
Elevated Cholesterol ◽  
Forearm Vascular Resistance

We investigated a change in vascular reactivity as a potential adaptive mechanism to chronic exercise. The study consisted of 2 separate protocols with 10 male athletes and 10 age-matched sedentary male control subjects participating in each. Protocol 1 investigated forearm blood flow responses to intra-arterial infusions of acetylcholine and sodium nitroprusside by use of venous occlusion plethysmography. Protocol 2 used identical techniques to study responses to norepinephrine, angiotensin II (ANG II), and NG-monomethyl-L-arginine (L-NMMA). The percent reduction in forearm vascular resistance to acetylcholine was significantly greater in the athletic compared with the sedentary group (multivariate analysis of variance for repeated measures, P = 0.03). Covariance analysis suggested that the lower total cholesterol level of the athletic group (P = 0.03) may contribute to their enhanced responsiveness to acetylcholine. There were no differences between athletic and sedentary groups in the forearm vascular resistance responses to norepinephrine, ANG II, sodium nitroprusside, or L-NMMA. These data support the hypothesis that long-term endurance training is associated with enhanced endothelium-dependent dilator reserve due to altered lipoprotein levels in athletes. This finding may have therapeutic application in conditions of elevated cholesterol and impaired vasodilator capacity including hypertension, hypercholesterolemia, atherosclerosis, and cardiac failure.

Role of endothelium-derived relaxing factors in the renal response to vasoactive agents in hypothyroid rats

2003 ◽  
Vol 285 (1) ◽  
pp. E182-E188 ◽  
Author(s):  
Juan Manuel Moreno ◽  
Rosemary Wangensteen ◽  
Juan Sainz ◽  
Isabel Rodríguez-Gomez ◽  
Virginia Chamorro ◽  
...  
Keyword(s):  
Vascular Reactivity ◽  
Ang Ii ◽  
Vasoactive Agents ◽  
Normal Response ◽  
No Donor ◽  
Increased Sensitivity ◽  
Renal Vascular ◽  
And Control ◽  
Renal Responses

This study analyzed the role of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) in the abnormal renal vascular reactivity of hypothyroid rats. Renal responses to vasoconstrictors [VC: phenylephrine (PHE) and ANG II] and vasodilators [VD: ACh, sodium nitroprusside (SNP), and papaverine (PV)] were studied in kidneys from control and hypothyroid rats under normal conditions and after NO or EDHF blockade. NO was blocked by the administration of Nω-nitro-l-arginine methyl ester (l-NAME) and EDHF by the administration of tetraethylammonium (TEA) or by an increased extracellular K+. The response to VC was also evaluated after endothelium removal. Hypothyroid kidneys showed reduced responsiveness to PHE and a normal response to ANG II. l-NAME and TEA administration produced an increased sensitivity to PHE and to ANG II in control preparations. l-NAME also increased the response to PHE in hypothyroid kidneys, but the differences between control and hypothyroid kidneys were maintained. TEA administration did not change the response to either VC in hypothyroid preparations. In endothelium-removed preparations, TEA was unable to increase pressor responsiveness to VC. Hypothyroid kidneys showed reduced responsiveness to ACh and SNP and normal response to PV. The differences between hypothyroid and control preparations in the responses to ACh and SNP were maintained after l-NAME or increased K+. In conclusion, this study shows that 1) the attenuated response to PHE in hypothyroidism is not related to an increased production of endothelium-derived relaxing factors NO and EDHF; 2) the response to VC in hypothyroid preparations is insensitive to EDHF blockade; and 3) hypothyroid preparations have a reduced reactivity to the NO donor, and NO-independent vasodilatation remains unaffected.

scholarly journals Endospanin 1 Determines the Balance of Leptin-Regulated Hypothalamic Functions

2018 ◽  
Vol 108 (2) ◽  
pp. 132-141
Author(s):  
Clara Roujeau ◽  
Ralf Jockers ◽  
Julie Dam
Keyword(s):  
Signaling Pathways ◽  
Intracellular Trafficking ◽  
Leptin Receptor ◽  
Leptin Resistance ◽  
Human Obesity ◽  
Leptin Signaling ◽  
Diet Induced Obesity ◽  
Important Regulator ◽  
Neuronal Plasma Membrane ◽  
Underlying Mechanisms

Endospanin 1 (Endo1), a protein encoded in humans by the same gene than the leptin receptor (ObR), and increased by diet-induced obesity, is an important regulator of ObR trafficking and cell surface exposure, determining leptin signaling strength. Defective intracellular trafficking of the leptin receptor to the neuronal plasma membrane has been proposed as a mechanism underlying the development of leptin resistance observed in human obesity. More recently, Endo1 has emerged as a mediator of “selective leptin resistance.” The underlying mechanisms of the latter are not completely understood, but the possibility of differential activation of leptin signaling pathways was suggested among others. In this respect, the expression level of Endo1 is crucial for the appropriate balance between different leptin signaling pathways and leptin functions in the hypothalamus and is likely participating in selective leptin resistance for the control of energy and glucose homeostasis.

scholarly journals Diabetes Enhances Vulnerability to Particulate Air Pollution–Associated Impairment in Vascular Reactivity and Endothelial Function

Circulation ◽  
2005 ◽  
Vol 111 (22) ◽  
pp. 2913-2920 ◽  
Author(s):  
Marie S. O’Neill ◽  
Aristidis Veves ◽  
Antonella Zanobetti ◽  
Jeremy A. Sarnat ◽  
Diane R. Gold ◽  
...  
Keyword(s):  
Air Pollution ◽  
Endothelial Function ◽  
Vascular Reactivity ◽  
Particulate Air Pollution

Abstract P288: Systemic Administration of an Angiotensin Type-2 Receptor Agonist Decreases Renal Regulatory T Cells

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Ellen E Gillis ◽  
Jennifer C Sullivan
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Critical Role ◽  
High Dose ◽  
Ang Ii ◽  
Osmotic Minipump ◽  
Angiotensin Type 2 Receptor ◽  
Angiotensin Type

There is increasing evidence supporting a critical role of the immune system in the development of hypertension. Our lab has previously reported sex differences in the renal T cell profile in both Spontaneously Hypertensive Rats (SHR) and Angiotensin II (Ang II) models of hypertension, with females having more anti-inflammatory regulatory T cells (Tregs) than males. Ang II has a well-defined role in the activation of pro-inflammatory T cells in hypertension via the angiotensin type-1 receptor (AT1R). Less is known about the role of the angiotensin type-2 receptor (AT2R) in the regulation of immune cells, although the AT2R has been shown to be cardioprotective and AT2R expression is greater in females than males. Based on the potential anti-hypertensive role of AT2Rs, we hypothesized that administration of an AT2R agonist, Compound 21 (C21), would increase renal Tregs, and this increase would be greater in females due to greater AT2R expression. Male and female SHR (10 weeks of age, n=3-4) were implanted with telemetry units for continuous monitoring of mean arterial pressure (MAP). Following 10 days of recovery, baseline MAP was recorded for 5 days. Rats were then divided into the following treatment groups: surgical controls, low dose C21 (150 ng/kg/min, sc by osmotic minipump), high dose C21 (300 ng/kg/min, sc by osmotic minipump). Kidneys were harvested after 2 weeks of treatment and flow cytometry was performed on whole kidney homogenates. MAP was not altered by C21 treatment in males (137±4 vs 134±4 vs 134±4 mmHg; n.s.) or females (128±2 vs 136±5 vs 134±4 mmHg; n.s.). Interestingly, despite having no effect on MAP, there was a significant decrease in renal CD3 + CD4 + FoxP3 + Tregs in females following both low and high doses of C21 (data expressed as % CD3 + CD4 + cells: 6±0.6 vs 3±0.6 vs 3.5±1.3 %, respectively; p=0.02). Tregs decrease in males following the high dose of C21 only (data expressed as % CD3 + CD4 + cells: 3.3±0.3 vs 3.3±0.5 vs 1.7±0.7 %, respectively; p=0.05). Total CD3 + T cells, CD3 + CD4 + T cells, and Th17 cells were not altered by C21 treatment. In conclusion, AT2R activation suppresses renal Tregs, and females are more sensitive than males. These data suggest a novel role for AT2R regulation in the kidney in hypertension.

Abstract 095: Human (Pro)renin Receptor Activation Induces an Angiotensin II-Independent Pressor Response Mediated by NADPH Oxidase 4 Activity

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Michelle N Sullivan ◽  
Wencheng Li ◽  
Curt D Sigmund ◽  
Yumei Feng
Keyword(s):  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Signaling Pathways ◽  
Pressor Response ◽  
Receptor Activation ◽  
Fold Change ◽  
Mrna Levels ◽  
Ang Ii ◽  
Proteolytic Activation ◽  
Nadph Oxidase 4

The binding of prorenin to the (pro)renin receptor (PRR) induces non-proteolytic activation of prorenin and generation of angiotensin II (Ang II). PRR activation can also induce Ang II-independent signaling pathways. However, whether Ang II-independent signaling pathways are critical for blood pressure (BP) regulation is not known. To address this question, we created transgenic mice that overexpress the human PRR (hPRR) selectively in neurons (Syn-hPRR). Activated human prorenin (hPRO) cannot cleave endogenous mouse angiotensinogen to generate Ang II. Therefore, administration of hPRO to Syn-hPRR mice can be used to examine Ang II-independent PRR signaling in BP regulation. Intracerebroventricular (ICV) infusion of hPRO increases BP in Syn-hPRR mice (ΔMAP 23 ± 4.6, n = 4) but has no effect on wildtype (WT) mice (ΔMAP 2 ± 0.8, n = 6). The hPRO-induced pressor response in Syn-hPRR mice is unaffected by co-infusion with the Ang II type 1 receptor blocker losartan (ΔMAP 19 ± 5.2, n = 8), suggesting that the response is independent of Ang II. Interestingly, co-infusion with an inhibitor of the reactive oxygen species-generating enzyme NADPH oxidase (NOX), diphenyleneiodonium, nearly abolishes the hPRO-induced pressor response in Syn-hPRR mice (ΔMAP 4.7 ± 1.0, n = 4), indicating that NOX activity is required. Additionally, we find that basal NOX activity is enhanced in the Syn-hPRR hypothalamus relative to WT mice (1.4 fold change). We next examined which NOX isoform is responsible for the hPRO-induced pressor response and enhanced activity. NOX4 mRNA levels are greater (2.7 ± 0.6 fold change), but NOX1 (1.2 ± 0.3 fold change) and NOX2 (1.2 ± 0.3 fold change) mRNA levels are not different, in the hypothalamus of Syn-hPRR compared to WT mice (n = 3). Adenovirus-mediated delivery of NOX2, NOX4, or a scrambled sequence shRNA was ICV injected in Syn-hPRR mice. After 7 days, we found that treatment with NOX2 (ΔMAP 20 ± 5.2) or scrambled (ΔMAP 23 ± 3.2) shRNA had no effect on the hPRO-induced pressor response (n = 5). However, the hPRO-induced increase in BP is attenuated in Syn-hPRR mice injected with NOX4 shRNA (ΔMAP 5.9 ± 2.8). Together, these data indicate that NOX4 mediates the Ang II-independent pressor response to activation of the human (pro)renin receptor in Syn-hPRR mice.

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