scholarly journals Altered Purinergic Receptor Sensitivity in Type 2 Diabetes-Associated Endothelial Dysfunction and Up4A-Mediated Vascular Contraction

2018 ◽  
Vol 19 (12) ◽  
pp. 3942 ◽  
Author(s):  
Ali Mahdi ◽  
Tong Jiao ◽  
Yahor Tratsiakovich ◽  
Jiangning Yang ◽  
Claes-Göran Östenson ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Function ◽  
Purinergic Receptor ◽  
Purinergic Signaling ◽  
Mesenteric Arteries ◽  
Vascular Contraction ◽  
Gk Rats ◽  
Vasoconstrictor Response

Purinergic signaling may be altered in diabetes accounting for endothelial dysfunction. Uridine adenosine tetraphosphate (Up4A), a novel dinucleotide substance, regulates vascular function via both purinergic P1 and P2 receptors (PR). Up4A enhances vascular contraction in isolated arteries of diabetic rats likely through P2R. However, the precise involvement of PRs in endothelial dysfunction and the vasoconstrictor response to Up4A in diabetes has not been fully elucidated. We tested whether inhibition of PRs improved endothelial function and attenuated Up4A-mediated vascular contraction using both aortas and mesenteric arteries of type 2 diabetic (T2D) Goto Kakizaki (GK) rats vs. control Wistar (WT) rats. Endothelium-dependent (EDR) but not endothelium-independent relaxation was significantly impaired in both aortas and mesenteric arteries from GK vs. WT rats. Non-selective inhibition of P1R or P2R significantly improved EDR in aortas but not mesenteric arteries from GK rats. Inhibition of A1R, P2X7R, or P2Y6R significantly improved EDR in aortas. Vasoconstrictor response to Up4A was enhanced in aortas but not mesenteric arteries of GK vs. WT rats via involvement of A1R and P2X7R but not P2Y6R. Depletion of major endothelial component nitric oxide enhanced Up4A-induced aortic contraction to a similar extent between WT and GK rats. No significant differences in protein levels of A1R, P2X7R, and P2Y6R in aortas from GK and WT rats were observed. These data suggest that altered PR sensitivity accounts for endothelial dysfunction in aortas in diabetes. Modulating PRs may represent a potential therapy for improving endothelial function.

scholarly journals Therapeutic Potential of Sunitinib in Ameliorating Endothelial Dysfunction in Type 2 Diabetic Rats

Pharmacology ◽  
2021 ◽  
pp. 1-7
Author(s):  
Ali Mahdi ◽  
Tong Jiao ◽  
Yahor Tratsiakovich ◽  
Bernhard Wernly ◽  
Jiangning Yang ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Wistar Rats ◽  
Microvascular Complications ◽  
Mesenteric Arteries ◽  
Tyrosine Kinase Receptor ◽  
Gk Rats ◽  
Glucose Levels ◽  
Arterial Blood

<b><i>Introduction:</i></b> Sunitinib, a multi-targeted tyrosine kinase receptor inhibitor used to treat renal-cell carcinoma and gastrointestinal stromal tumor, was recently shown to have a beneficial effect on metabolism in type 2 diabetes (T2D). Endothelial dysfunction is a key factor behind macro- and microvascular complications in T2D. The effect of sunitinib on endothelial function in T2D remains, however, unclear. We therefore tested the hypothesis that sunitinib ameliorates endothelial dysfunction in T2D. <b><i>Methods:</i></b> Sunitinib (2 mg/kg/day, by gavage) was administered to T2D Goto-Kakizaki (GK) rats for 6 weeks, while water was given to GK and Wistar rats as controls. Hemodynamic, inflammatory, and metabolic parameters as well as endothelial function were measured. <b><i>Results:</i></b> Systolic, mean arterial blood pressures, plasma tumor necrosis factor α levels, kidney weight to body weight (BW) ratio, and glucose levels were higher, while BW was lower in GK rats than in Wistar rats. Six-week treatment with sunitinib in GK rats did not affect these parameters but suppressed the increase in glucose levels. Endothelium-dependent relaxations were reduced in both aortas and mesenteric arteries isolated from GK as compared to Wistar rats, which was markedly reversed in both types of arteries from GK rats treated with sunitinib. <b><i>Conclusions:</i></b> This study demonstrates that sunitinib has a glucose-lowering effect and ameliorates endothelial dysfunction in both conduit and resistance arteries of GK rats.

Endothelial dysfunction in Type 2 diabetes correlates with deregulated expression of the tail-anchored membrane protein SLMAP

2005 ◽  
Vol 289 (1) ◽  
pp. H206-H211 ◽  
Author(s):  
Hong Ding ◽  
Andrew G. Howarth ◽  
Malarvannan Pannirselvam ◽  
Todd J. Anderson ◽  
David L. Severson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Microvascular Disease ◽  
Mesenteric Arteries ◽  
Mrna Levels ◽  
Important Indicator ◽  
Membrane Function

The Type 2 diabetic db/ db mouse experiences vascular dysfunction typified by changes in the contraction and relaxation profiles of small mesenteric arteries (SMAs). Contractions of SMAs from the db/ db mouse to the α1-adrenoceptor agonist phenylephrine (PE) were significantly enhanced, and acetylcholine (ACh)-induced relaxations were significantly depressed. Drug treatment of db/ db mice with a nonthiazolidinedione peroxisome prolifetor-activated receptor-γ agonist and insulin sensitizing agent 2-[2-(4-phenoxy-2-propylphenoxy)ethyl]indole-5-acetic acid (COOH) completely prevented the changes in endothelium-dependent relaxation, but, with the discontinuation of therapy, endothelial dysfunction returned. Dysfunctional SMAs were found to specifically upregulate the expression of a 35-kDa isoform of sarcolemmal membrane-associated protein (SLMAP), which is a component of the excitation-contraction coupling apparatus and implicated in the regulation of membrane function in muscle cells. Real-time PCR revealed high SLMAP mRNA levels in the db/ db microvasculature, which were markedly downregulated during COOH treatment but elevated again when drug therapy was discontinued. These data reveal that the microvasculature in db/ db mice undergoes significant changes in vascular function with the endothelial component of vascular dysfunction specifically correlating with the overexpression of SLMAP. Thus changes in SLMAP expression may be an important indicator for microvascular disease associated with Type 2 diabetes.

scholarly journals NADPH oxidase 4 has a crucial impact on the microcirculation of hypercholesteremic LDL receptor deficient mice

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
P Diaba-Nuhoho ◽  
A Shahid ◽  
C Brunssen ◽  
H Morawietz ◽  
H Brendel
Keyword(s):  
Blood Pressure ◽  
Endothelial Dysfunction ◽  
Mouse Model ◽  
Nadph Oxidase ◽  
Endothelial Function ◽  
Vascular Function ◽  
Mesenteric Arteries ◽  
Resistance Arteries ◽  
Enos Expression ◽  
Small Resistance

Abstract Introduction NADPH oxidase (NOX) 4-generated H2O2 has anti-atherosclerotic properties in conduit arteries like the aorta and carotids. However, the role of NOX4 on vascular function of small resistance arteries and blood pressure in a mouse model of familial hypercholesterolemia is unknown. Purpose We evaluated whether NOX4-generated H2O2 might play a role in perivascular adipose tissue of the thoracic aorta (tPVAT) and small resistance arteries on vascular function in a mouse model of familial hypercholesterolemia. Methods Aortic segments and mesenteric arteries from 26-week-old Ldlr−/− and Nox4−/− / Ldlr−/− mice were analysed by Mulvany myograph. In addition, vascular contraction and relaxation was analysed in the presence of L-NAME and catalase. Analysis of mRNA expression was performed in murine and human tissue by quantitative real-time PCR. Blood pressure was detected by tail cuff method in conscious, trained mice. Results Loss of NOX4 led to severe endothelial dysfunction in mesenteric arteries of Ldlr−/− mice. Blocking of NO synthases with L-NAME led to decreased endothelial relaxation in Ldlr−/− mice at the level of Nox4−/− / Ldlr−/− mice. However, incubation with L-NAME did not worsen the established endothelial dysfunction of the mesenteric arteries from Nox4−/− / Ldlr−/− mice. These results are strikingly different from the aorta, where inhibition of NO synthases led to a similarly impaired endothelial relaxation in both mouse strains. We detected a similar eNOS expression in the aorta of Ldlr−/− and Nox4−/− / Ldlr−/−, but a reduced eNOS expression in the mesenteric arteries of Nox4−/− / Ldlr−/− mice. H2O2 can induce eNOS expression. Therefore, we analysed the vascular function after catalase incubation and again found a significant reduction of endothelial function in the mesenteric arteries of Ldlr−/− mice. Finally, we analysed blood pressure of these mice and did not observe differences in systolic blood pressure, despite significant differences in endothelial function of resistant arteries. Conclusion NOX4 protects against severe endothelial dysfunction in the mesenteric artery in a model of hypercholesterolemia. FUNDunding Acknowledgement Type of funding sources: Other. Main funding source(s): Ghanaian-German postgraduate training scholarship program (DAAD)

scholarly journals Erythrocytes Induce Endothelial Injury in Type 2 Diabetes Through Alteration of Vascular Purinergic Signaling

2020 ◽  
Vol 11 ◽  
Author(s):  
Ali Mahdi ◽  
Yahor Tratsiakovich ◽  
John Tengbom ◽  
Tong Jiao ◽  
Lara Garib ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endothelial Dysfunction ◽  
Ex Vivo ◽  
Purinergic Receptor ◽  
Purinergic Signaling ◽  
Vascular Dysfunction ◽  
Endothelium Dependent Relaxation ◽  
Human Rbcs

It is well established that altered purinergic signaling contributes to vascular dysfunction in type 2 diabetes (T2D). Red blood cells (RBCs) serve as an important pool for circulating ATP and the release of ATP from RBCs in response to physiological stimuli is impaired in T2D. We recently demonstrated that RBCs from patients with T2D (T2D RBC) serve as key mediators of endothelial dysfunction. However, it remains unknown whether altered vascular purinergic signaling is involved in the endothelial dysfunction induced by dysfunctional RBCs in T2D. Here, we evaluated acetylcholine-induced endothelium-dependent relaxation (EDR) of isolated rat aortas after 18 h ex vivo co-incubation with human RBCs, and aortas of healthy recipient rats 4 h after in vivo transfusion with RBCs from T2D Goto-Kakizaki (GK) rats. Purinergic receptor (PR) antagonists were applied in isolated aortas to study the involvement of PRs. EDR was impaired in aortas incubated with T2D RBC but not with RBCs from healthy subjects ex vivo, and in aortas of healthy rats after transfusion with GK RBCs in vivo. The impairment in EDR by T2D RBC was attenuated by non-selective P1R and P2R antagonism, and specific A1R, P2X7R but not P2Y6R antagonism. Transfusion with GK RBCs in vivo impaired EDR in aortas of recipient rats, an effect that was attenuated by A1R, P2X7R but not P2Y6R antagonism. In conclusion, RBCs induce endothelial dysfunction in T2D via vascular A1R and P2X7R but not P2Y6R. Targeting vascular purinergic singling may serve as a potential therapy to prevent endothelial dysfunction induced by RBCs in T2D.

scholarly journals GLP-1 Agonists Liraglutide Improved Vascular Endothelial Function in Type 2 Diabetes Rats

2020 ◽  
Vol 2 (2) ◽  
pp. 46-55
Author(s):  
Li X ◽  
Wu W ◽  
Wang Y ◽  
Zhang X ◽  
Feng X ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Mesenteric Arteries ◽  
Vascular Endothelial ◽  
Vascular Endothelial Dysfunction ◽  
Vascular Endothelial Function

Objective: Liraglutide (LIRA), a Glucagon-like peptide-1 (GLP-1) receptor agonist, showed potential vascular protective effects with the mechanism remained incompletely understood. Therefore, this study aimed to investigate whether LIRA exerts its effect on vascular endothelial function in rats with type 2 diabetes mellitus (T2DM) via caveolin-1/ endothelial oxide synthase (eNOS) expression. Methods: T2DM rats were used as study subjects and randomly divided into four groups: 1) Veh group, 2) Veh+LIRA group, 3) T2DM group, and 4) T2DM+LIRA group. All rats received either saline or LIRA 0.2 mg/kg (by i.p. injection) per day for 4 weeks. After the model was successfully established, vascular endothelial function was determined the effect of vasodilator to mesenteric artery rings. Immunofluorescence and western blot were performed to understand the molecular mechanism. Cultured HUVECs with small interfering RNA (siRNA) under high glucose (HG), NO concentration, and western blot were performed to understand the molecular mechanism between LIRA and vascular endothelial function. Results: Based on our results, the LIRA reduced hyperglycemia and ameliorated vascular endothelial dysfunction in type 2 diabetic mice. LIRA activated eNOS phosphorylation, suppressing oxidative stress and enhancing endothelium-dependent vasorelaxation of mesenteric arteries. Besides, from its anti-oxidative capacity, LIRA activated eNOS to dilate the mesenteric arteries via the downregulation of Cav-1. Conclusion: LIRA ameliorates vascular endothelial dysfunction in rats with type 2 diabetes mellitus via anti-oxidative and activated eNOS by downregulated Cav-1.

scholarly journals An anxiolytic drug buspirone ameliorates hyperglycemia and endothelial dysfunction in type 2 diabetic rat model

2020 ◽  
Vol 45 (4) ◽  
pp. 397-404
Author(s):  
Tugba Gurpinar Çavuşoğlu ◽  
Ertan Darıverenli ◽  
Kamil Vural ◽  
Nuran Ekerbicer ◽  
Cevval Ulman ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Endothelial Dysfunction ◽  
Vascular Function ◽  
Fasting Blood Glucose ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Insulin Levels ◽  
Type 2 Diabetic

AbstractObjectivesType 2 diabetes is a common metabolic disease and anxiety disorders are very common among diabetics. Buspirone is used in the treatment of anxiety, also having blood glucose-lowering effects. The aim of the study was to investigate the effects of buspirone on the glucose and lipid metabolism as well as vascular function in type 2 diabetic rats.MethodsA type 2-diabetic model was induced through a high-fat diet for eight weeks followed by the administration of low-dose streptozotocin (35 mg/kg, intraperitoneal) in rats. Buspirone was given at two different doses (1.5 mg/kg/d and 5 mg/kg/d) and combined with metformin (300 mg/kg/d). The fasting glucose and insulin levels, lipid profile were analyzed, and vascular response measured from the thoracic aorta was also evaluated.ResultsBoth doses of buspirone caused a significant improvement in fasting blood glucose levels. In particular, the buspirone treatment, combined with metformin, improved endothelial dysfunction and was found to be correlated with decreased nitrate/nitrite levels.ConclusionsBuspirone may be effective in the treatment of type 2 diabetes, either alone or in combination with other treatments, particularly in terms of endothelial dysfunction, inflammation and impaired blood glucose, and insulin levels.

Fenofibrate improves endothelial function in the brachial artery and forearm resistance arterioles of statin-treated Type 2 diabetic patients

2010 ◽  
Vol 118 (10) ◽  
pp. 607-615 ◽  
Author(s):  
Sandra J. Hamilton ◽  
Gerard T. Chew ◽  
Timothy M.E. Davis ◽  
Gerald F. Watts
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Statin Therapy ◽  
Brachial Artery ◽  
Ldl Cholesterol ◽  
Density Lipoprotein ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Type 2 Diabetic

Dyslipidaemia contributes to endothelial dysfunction and CVD (cardiovascular disease) in Type 2 diabetes mellitus. While statin therapy reduces CVD in these patients, residual risk remains high. Fenofibrate corrects atherogenic dyslipidaemia, but it is unclear whether adding fenofibrate to statin therapy lowers CVD risk. We investigated whether fenofibrate improves endothelial dysfunction in statin-treated Type 2 diabetic patients. In a cross-over study, 15 statin-treated Type 2 diabetic patients, with LDL (low-density lipoprotein)-cholesterol <2.6 mmol/l and endothelial dysfunction [brachial artery FMD (flow-mediated dilatation) <6.0%] were randomized, double-blind, to fenofibrate 145 mg/day or matching placebo for 12 weeks, with 4 weeks washout between treatment periods. Brachial artery FMD and endothelium-independent NMD (nitrate-mediated dilatation) were measured by ultrasonography at the start and end of each treatment period. PIFBF (post-ischaemic forearm blood flow), a measure of microcirculatory endothelial function, and serum lipids, lipoproteins and apo (apolipoprotein) concentrations were also measured. Compared with placebo, fenofibrate increased FMD (mean absolute 2.1±0.6 compared with −0.3±0.6%, P=0.04), but did not alter NMD (P=0.75). Fenofibrate also increased maximal PIFBF {median 3.5 [IQR (interquartile range) 5.8] compared with 0.3 (2.1) ml/100 ml/min, P=0.001} and flow debt repayment [median 1.0 (IQR 3.5) compared with −1.5 (3.0) ml/100 ml, P=0.01]. Fenofibrate lowered serum cholesterol, triacylgycerols (triglycerides), LDL-cholesterol, apoB-100 and apoC-III (P≤0.03), but did not alter HDL (high-density lipoprotein)-cholesterol or apoA-I. Improvement in FMD was inversely associated with on-treatment LDL-cholesterol (r=−0.61, P=0.02) and apoB-100 (r=−0.54, P=0.04) concentrations. Fenofibrate improves endothelial dysfunction in statin-treated Type 2 diabetic patients. This may relate partly to enhanced reduction in LDL-cholesterol and apoB-100 concentrations.

Sex Differences in the Relation Between Frailty and Endothelial Dysfunction in Old Mice

2021 ◽  
Author(s):  
Jazmin A Cole ◽  
Mackenzie N Kehmeier ◽  
Bradley R Bedell ◽  
Sahana Krishna Kumaran ◽  
Grant D Henson ◽  
...  
Keyword(s):  
Sex Differences ◽  
Endothelial Function ◽  
Vascular Function ◽  
Mesenteric Artery ◽  
Frailty Index ◽  
Mesenteric Arteries ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice ◽  
Age Related

Abstract Vascular endothelial function declines with age on average, but there is high variability in the magnitude of this decline within populations. Measurements of frailty, known as frailty index (FI), can be used as surrogates for biological age, but it is unknown if frailty relates to the age-related decline in vascular function. To examine this relation, we studied young (4-9 months) and old (23-32 months) C57BL6 mice of both sexes. We found that FI was greater in old compared with young mice, but did not differ between old male and female mice. Middle cerebral artery (MCA) and mesenteric artery endothelium-dependent dilation (EDD) also did not differ between old male and female mice; however, there were sex differences in the relations between FI and EDD. For the MCA, FI was inversely related to EDD among old female mice, but not old male mice. In contrast, for the mesenteric artery, FI was inversely related to EDD among old male mice, but not old female mice. A higher FI was related to a greater improvement in EDD with the superoxide scavenger TEMPOL in the MCAs for old female mice and in the mesenteric arteries for old male mice. FI related to mesenteric artery gene expression negatively for extracellular superoxide dismutase (Sod3) and positively for interleukin-1β (Il1b). In summary, we found that the relation between frailty and endothelial function is dependent on sex and the artery examined. Arterial oxidative stress and pro-inflammatory signaling are potential mediators of the relations of frailty and endothelial function.

Sleep deprivation and endothelial function: reconciling seminal evidence with recent perspectives

2021 ◽  
Vol 320 (1) ◽  
pp. H29-H35
Author(s):  
Joshua M. Cherubini ◽  
Jem L. Cheng ◽  
Jennifer S. Williams ◽  
Maureen J. MacDonald
Keyword(s):  
Cardiovascular Disease ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Sleep Deprivation ◽  
Vascular Function ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Health Concern ◽  
Short Sleep ◽  
Inadequate Sleep

Sleep is critical for the maintenance of physiological homeostasis and, as such, inadequate sleep beckons a myriad of pathologies. Sleep deprivation is a growing health concern in contemporary society since short sleep durations are associated with increased cardiovascular disease risk and atherosclerotic plaque development. Vascular endothelial dysfunction is an antecedent to atherosclerosis and cardiovascular disease. Herein, we review seminal literature indicating that short sleep durations attenuate endothelial function and explore more recent evidence indicating that sleep deprivation perturbs autonomic balance and the circadian rhythmicity of peripheral vascular clock components. We further examine literature that indicates a mechanistic link between short sleep duration and endothelial dysfunction and subsequent morbidity. Understanding the mechanisms that regulate endothelial function in the context of sleep deprivation facilitates the development and optimization of interventions, such as exercise, that mitigate the ramifications of inadequate sleep on vascular function and cardiovascular health. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/sleep-deprivation-and-endothelial-function/

Effects of polycythemia on systemic endothelial function in chronic hypoxic lung disease

2011 ◽  
Vol 110 (5) ◽  
pp. 1196-1203 ◽  
Author(s):  
Laurent Boyer ◽  
Vicky Chaar ◽  
Gabriel Pelle ◽  
Bernard Maitre ◽  
Christos Chouaid ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Brachial Artery ◽  
Blood Viscosity ◽  
Vascular Function ◽  
Venous Occlusion ◽  
Chronic Obstructive ◽  
Brachial Artery Diameter ◽  
Obstructive Pulmonary Disease ◽  
Vasoconstrictor Response ◽  
No Release

Chronic obstructive pulmonary disease (COPD) is a major risk factor for cardiovascular disease. Polycythemia, a common complication of hypoxic COPD, may affect systemic vascular function by altering blood viscosity, vessel wall shear stress (WSS), and endothelium-derived nitric oxide (NO) release. Here, we evaluated the effects of hypoxia-related polycythemia on systemic endothelial function in patients with COPD. We investigated blood viscosity, WSS, and endothelial function in 15 polycythemic and 13 normocythemic patients with COPD of equal severity, by recording brachial artery diameter variations in response to hyperemia and by using venous occlusion plethysmography (VOP) to measure forearm blood flow (FBF) responses to a brachial artery infusion of acetylcholine (ACh), bradykinin (BK), sodium nitroprusside (SNP), substance P (SP), isoptin, and N-monomethyl-l-arginine (l-NMMA). At baseline, polycythemic patients had higher blood viscosity and larger brachial artery diameter than normocythemic patients but similar calculated WSS. Flow-mediated brachial artery vasodilation was increased in the polycythemic patients, in proportion to the hemoglobin levels. ACh-induced vasodilation was markedly impaired in the polycythemic patients and negatively correlated with hemoglobin levels. FBF responses to endothelium- (BK, SP) and non-endothelium-dependent (SNP, isoptin) vasodilators were not significantly different between the two groups. l-NMMA infusion induced a similar vasoconstrictor response in both groups, in accordance with their similar baseline WSS. In conclusion, systemic arteries in polycythemic patients adjust appropriately to chronic or acute WSS elevations by appropriate basal and stimulated NO release. Overall, our results suggest that moderate polycythemia has no adverse effect on vascular function in COPD.

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