Previous gestational diabetes impairs long-term endothelial function in a mouse model of complicated pregnancy

2010 ◽  
Vol 299 (3) ◽  
pp. R862-R870 ◽  
Author(s):  
Joanna L. Stanley ◽  
Sowndramalingam Sankaralingam ◽  
Philip N. Baker ◽  
Sandra T. Davidge
Keyword(s):  
Endothelial Dysfunction ◽  
Gestational Diabetes ◽  
Mouse Model ◽  
Endothelial Function ◽  
Fluorescence Intensity ◽  
Mean Fluorescence Intensity ◽  
Mesenteric Arteries ◽  
Superoxide Production ◽  
Increased Risk

Women who develop gestational diabetes mellitis (GDM) display endothelial dysfunction up to 1 yr after pregnancy, despite a return to normoglycemia. It is unknown whether this dysfunction was preexisting or whether GDM pregnancy leads to long-term endothelial dysfunction. A mouse model that spontaneously develops GDM ( Lepr db/+) was used to determine whether the endothelial dysfunction that develops during GDM is evident in later life. Heterozygous and wild-type (WT) controls were allowed to litter once, then age to 9–10 mo, and were compared with virgin controls. Vascular function of small mesenteric arteries was assessed using wire myography. Concentration response curves to the thromboxane A2mimetic U46619 and the endothelium-dependent vasodilator methacholine were constructed. Superoxide production and peroxynitrite formation was also measured. Mice with previous GDM displayed blood glucose concentrations similar to previously pregnant WT mice (8.0 ± 0.1 vs. 7.1 ± 0.3 mmol/l, P > 0.05). Arteries from mice with previous GDM displayed increased sensitivity to U46619 (EC50 5.2 ± 0.7 vs. 45.2 ± 1.0 nmol/l, P < 0.01) and impaired endothelium-dependent relaxation compared with WT controls (29 ± 8 vs. 58 ± 16 percent relaxation, P < 0.05). This was associated with increased superoxide production (93.3 ± 2.3 vs. 64.6 ± 1.6 mean fluorescence intensity, P < 0.001) and increased peroxynitrite formation (173.5 ± 11.0 vs. 57.4 ± 16.2 mean fluorescence intensity, P < 0.01) compared with virgin controls. In summary, endothelial dysfunction was evident in mice with previous GDM compared with previously healthy pregnant mice or virgin controls. These data suggest that GDM affects endothelial function and may contribute to an increased risk of cardiovascular disease.

scholarly journals Endothelial dysfunction in individuals born after fetal growth restriction: cardiovascular and renal consequences and preventive approaches

2017 ◽  
Vol 8 (4) ◽  
pp. 448-464 ◽  
Author(s):  
C. Yzydorczyk ◽  
J. B. Armengaud ◽  
A. C. Peyter ◽  
H. Chehade ◽  
F. Cachat ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Function ◽  
Growth Restriction ◽  
Systemic Hypertension ◽  
Renal Diseases ◽  
Long Term Effects ◽  
Epigenetic Biomarkers ◽  
Increased Risk

Individuals born after intrauterine growth restriction (IUGR) have an increased risk of perinatal morbidity/mortality, and those who survive face long-term consequences such as cardiovascular-related diseases, including systemic hypertension, atherosclerosis, coronary heart disease and chronic kidney disease. In addition to the demonstrated long-term effects of decreased nephron endowment and hyperactivity of the hypothalamic–pituitary–adrenal axis, individuals born after IUGR also exhibit early alterations in vascular structure and function, which have been identified as key factors of the development of cardiovascular-related diseases. The endothelium plays a major role in maintaining vascular function and homeostasis. Therefore, it is not surprising that impaired endothelial function can lead to the long-term development of vascular-related diseases. Endothelial dysfunction, particularly impaired endothelium-dependent vasodilation and vascular remodeling, involves decreased nitric oxide (NO) bioavailability, impaired endothelial NO synthase functionality, increased oxidative stress, endothelial progenitor cells dysfunction and accelerated vascular senescence. Preventive approaches such as breastfeeding, supplementation with folate, vitamins, antioxidants, L-citrulline, L-arginine and treatment with NO modulators represent promising strategies for improving endothelial function, mitigating long-term outcomes and possibly preventing IUGR of vascular origin. Moreover, the identification of early biomarkers of endothelial dysfunction, especially epigenetic biomarkers, could allow early screening and follow-up of individuals at risk of developing cardiovascular and renal diseases, thus contributing to the development of preventive and therapeutic strategies to avert the long-term effects of endothelial dysfunction in infants born after IUGR.

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 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.

Total Hip Replacement Provokes Endothelial Dysfunction

Angiology ◽  
2018 ◽  
Vol 69 (10) ◽  
pp. 871-877 ◽  
Author(s):  
Peter Poredos ◽  
Ana Mavric ◽  
Lara Leben ◽  
Pavel Poredos ◽  
Mateja Kaja Jezovnik
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Total Hip Replacement ◽  
Postoperative Period ◽  
Hip Replacement ◽  
Hospital Length Of Stay ◽  
Average Hospital ◽  
Total Hip ◽  
Increased Risk ◽  
Cardiovascular Homeostasis

Surgery represents an increased risk of different perioperative complications. Endothelial function (EF) is a key mechanism responsible for cardiovascular homeostasis and is involved in thromboembolic complications. We aimed to follow changes of EF in an early postoperative period in patients undergoing total hip replacement (THR). Endothelial function was assessed noninvasively in 70 consecutive patients who underwent an elective THR under spinal anesthesia. Flow-mediated dilation (FMD) and low flow-mediated constriction capability of the brachial artery, which are indicators of EF were measured before the operation (baseline), 24 hours after the operative procedure, and 5 to 7 days postoperatively. Baseline FMD was 12.3% and decreased a day after surgery to 7.3% ( P < .001). After 5 to 7 days, it gradually increased to 9.2%. However, on average, it was lower than before surgery ( P < .001). The median duration of THR was 85.0 (65.0-100.0) minutes, the average hospital length of stay was 7 days. Total hip replacement is associated with an immediate decrease in FMD which remains significantly decreased 5 to 7 days after the surgery compared with the preoperative value. These results indicate that surgery provokes endothelial dysfunction and deteriorates cardiovascular homeostasis. This effect could be involved in cardiovascular complications in the postoperative period.

scholarly journals Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans

2019 ◽  
Vol 40 (30) ◽  
pp. 2534-2547 ◽  
Author(s):  
Dick H J Thijssen ◽  
Rosa Maria Bruno ◽  
Anke C C M van Mil ◽  
Sophie M Holder ◽  
Francesco Faita ◽  
...  
Keyword(s):  
Endothelial Function ◽  
Clinical Symptoms ◽  
Clinical Manifestations ◽  
Arterial Disease ◽  
Expert Consensus ◽  
Flow Mediated Dilation ◽  
Pharmacological Interventions ◽  
Increased Risk ◽  
Long Term Impact

Abstract Endothelial dysfunction is involved in the development of atherosclerosis, which precedes asymptomatic structural vascular alterations as well as clinical manifestations of cardiovascular disease (CVD). Endothelial function can be assessed non-invasively using the flow-mediated dilation (FMD) technique. Flow-mediated dilation represents an endothelium-dependent, largely nitric oxide (NO)-mediated dilatation of conduit arteries in response to an imposed increase in blood flow and shear stress. Flow-mediated dilation is affected by cardiovascular (CV) risk factors, relates to coronary artery endothelial function, and independently predicts CVD outcome. Accordingly, FMD is a tool for examining the pathophysiology of CVD and possibly identifying subjects at increased risk for future CV events. Moreover, it has merit in examining the acute and long-term impact of physiological and pharmacological interventions in humans. Despite concerns about its reproducibility, the available evidence shows that highly reliable FMD measurements can be achieved when specialized laboratories follow standardized protocols. For this purpose, updated expert consensus guidelines for the performance of FMD are presented, which are based on critical appraisal of novel technical approaches, development of analysis software, and studies exploring the physiological principles underlying the technique. Uniformity in FMD performance will (i) improve comparability between studies, (ii) contribute to construction of reference values, and (iii) offer an easy accessible and early marker of atherosclerosis that could complement clinical symptoms of structural arterial disease and facilitate early diagnosis and prediction of CVD outcomes.

scholarly journals Role of TNF-α-induced reactive oxygen species in endothelial dysfunction during reperfusion injury

2008 ◽  
Vol 295 (6) ◽  
pp. H2242-H2249 ◽  
Author(s):  
Xue Gao ◽  
Hanrui Zhang ◽  
Souad Belmadani ◽  
Junxi Wu ◽  
Xiangbin Xu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endothelial Dysfunction ◽  
Myocardial Ischemia ◽  
Endothelial Function ◽  
Xanthine Oxidase ◽  
Reactive Oxygen ◽  
Neutrophil Activation ◽  
Superoxide Production ◽  
Oxygen Species ◽  
Tnf Α

We hypothesized that neutralization of TNF-α at the time of reperfusion exerts a salubrious role on endothelial function and reduces the production of reactive oxygen species. We employed a mouse model of myocardial ischemia-reperfusion (I/R, 30 min/90 min) and administered TNF-α neutralizing antibodies at the time of reperfusion. I/R elevated TNF-α expression (mRNA and protein), whereas administration of anti-TNF-α before reperfusion attenuated TNF-α expression. We detected TNF-α expression in vascular smooth muscle cells, mast cells, and macrophages, but not in the endothelial cells. I/R induced endothelial dysfunction and superoxide production. Administration of anti-TNF-α at the onset of reperfusion partially restored nitric oxide-mediated coronary arteriolar dilation and reduced superoxide production. I/R increased the activity of NAD(P)H oxidase and of xanthine oxidase and enhanced the formation of nitrotyrosine residues in untreated mice compared with shams. Administration of anti-TNF-α before reperfusion blocked the increase in activity of these enzymes. Inhibition of xanthine oxidase (allopurinol) or NAD(P)H oxidase (apocynin) improved endothelium-dependent dilation and reduced superoxide production in isolated coronary arterioles following I/R. Interestingly, I/R enhanced superoxide generation and reduced endothelial function in neutropenic animals and in mice treated with a neutrophil NAD(P)H oxidase inhibitor, indicating that the effects of TNF-α are not through neutrophil activation. We conclude that myocardial ischemia initiates TNF-α expression, which induces vascular oxidative stress, independent of neutrophil activation, and leads to coronary endothelial dysfunction.

scholarly journals Diabetes in Pregnancy and MicroRNAs: Promises and Limitations in Their Clinical Application

2018 ◽  
Vol 4 (4) ◽  
pp. 32 ◽  
Author(s):  
Adriana Ibarra ◽  
Begoña Vega-Guedes ◽  
Yeray Brito-Casillas ◽  
Ana Wägner
Keyword(s):  
Gestational Diabetes ◽  
Maternal Diabetes ◽  
Long Term Outcomes ◽  
Pregnant Rats ◽  
Diagnostic Biomarkers ◽  
Obesity And Diabetes ◽  
Increased Risk ◽  
Short And Long Term

Maternal diabetes is associated with an increased risk of complications for the mother and her offspring. The latter have an increased risk of foetal macrosomia, hypoglycaemia, respiratory distress syndrome, preterm delivery, malformations and mortality but also of life-long development of obesity and diabetes. Epigenetics have been proposed as an explanation for this long-term risk, and microRNAs (miRNAs) may play a role, both in short- and long-term outcomes. Gestation is associated with increasing maternal insulin resistance, as well as β-cell expansion, to account for the increased insulin needs and studies performed in pregnant rats support a role of miRNAs in this expansion. Furthermore, several miRNAs are involved in pancreatic embryonic development. On the other hand, maternal diabetes is associated with changes in miRNA both in maternal and in foetal tissues. This review aims to summarise the existing knowledge on miRNAs in gestational and pre-gestational diabetes, both as diagnostic biomarkers and as mechanistic players, in the development of gestational diabetes itself and also of short- and long-term complications for the mother and her offspring.

scholarly journals The impact of gestational diabetes and maternal obesity on the mother and her offspring

2010 ◽  
Vol 1 (4) ◽  
pp. 208-215 ◽  
Author(s):  
P. M. Catalano
Keyword(s):  
Insulin Resistance ◽  
Gestational Diabetes ◽  
Glucose Intolerance ◽  
Maternal Obesity ◽  
Insulin Response ◽  
Obese Women ◽  
Increased Risk ◽  
Short And Long Term ◽  
The Impact

Thein uteromaternal metabolic environment is important relative to both short and long term development of the offspring. Although poor fetal growth remains a significant factor relative to long-term outcome, fetal overgrowth is assuming greater importance because of the increase in obesity in the world’s populations. Maternal obesity and gestational diabetes are the most common metabolic complications of pregnancy related to fetal overgrowth and more specifically adiposity.Women with gestational diabetes have increased insulin resistance and inadequate insulin response compared with weight-matched controls. Gestational diabetes increases the risk of maternal hypertensive disease (preeclampsia) as well as cesarean delivery. At birth the neonate has increased adiposity and is at risk for birth injury. Multiple studies have reported that children of women with gestational diabetes have a greater prevalence childhood obesity and glucose intolerance; even at glucose concentrations less than currently used to define gestational diabetes, compared with normoglycemic women.Obese women also have increased insulin resistance, insulin response and inflammatory cytokines compared with average weight women both before and during pregnancy. They too are at increased risk for the metabolic syndrome-like disorders during pregnancy that is hypertension, hyperlipidemia, glucose intolerance and coagulation disorders. Analogous to women with gestational diabetes, neonates of obese women are heavier at delivery because of increased fat and not lean body mass. Similarly, these children have an increased risk of childhood adiposity and metabolic dysregulation. Hence, the preconceptional and perinatal period offers a unique opportunity to modify both short and long term risks for both the woman and her offspring.

scholarly journals Proton Pump Inhibitors Accelerate Endothelial Senescence

2016 ◽  
Vol 118 (12) ◽  
Author(s):  
Gautham Yepuri ◽  
Roman Sukhovershin ◽  
Timo Z. Nazari-Shafti ◽  
Michael Petrascheck ◽  
Yohannes T. Ghebre ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Chronic Exposure ◽  
Vascular Dysfunction ◽  
Term Effect ◽  
Long Term Effect ◽  
Increased Risk ◽  
Neurological Morbidity

Rationale: Proton pump inhibitors (PPIs) are popular drugs for gastroesophageal reflux, which are now available for long-term use without medical supervision. Recent reports suggest that PPI use is associated with cardiovascular, renal, and neurological morbidity. Objective: To study the long-term effect of PPIs on endothelial dysfunction and senescence and investigate the mechanism involved in PPI-induced vascular dysfunction. Methods and Results: Chronic exposure to PPIs impaired endothelial function and accelerated human endothelial senescence by reducing telomere length. Conclusions: Our data may provide a unifying mechanism for the association of PPI use with increased risk of cardiovascular, renal, and neurological morbidity and mortality.

scholarly journals Pulmonary Hypertension Secondary to COPD

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Adil Shujaat ◽  
Abubakr A. Bajwa ◽  
James D. Cury
Keyword(s):  
Pulmonary Hypertension ◽  
Endothelial Dysfunction ◽  
Pulmonary Artery ◽  
Exercise Capacity ◽  
Oxygen Therapy ◽  
Pulmonary Vasodilators ◽  
Increased Risk ◽  
Acute Exacerbations ◽  
Long Term Oxygen Therapy

The development of pulmonary hypertension in COPD adversely affects survival and exercise capacity and is associated with an increased risk of severe acute exacerbations. Unfortunately not all patients with COPD who meet criteria for long term oxygen therapy benefit from it. Even in those who benefit from long term oxygen therapy, such therapy may reverse the elevated pulmonary artery pressure but cannot normalize it. Moreover, the recent discovery of the key roles of endothelial dysfunction and inflammation in the pathogenesis of PH provides the rationale for considering specific pulmonary vasodilators that also possess antiproliferative properties and statins.

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