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

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.

Download Full-text

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00200.2010 ◽

2010 ◽

Vol 299 (3) ◽

pp. R862-R870 ◽

Cited By ~ 9

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.

Download Full-text

Abstract 1148: Local Hypercoagulability and Endothelial Dysfunction after Sirolimus-Eluting Stent Implantation: Implication for Late Stent Thrombosis

Circulation ◽

10.1161/circ.118.suppl_18.s_651 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Koji Yamaguchi ◽

Tetsuzo Wakatsuki ◽

Toshiyuki Niki ◽

Kenya Kusunose ◽

Kunihiko Koshiba ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Endothelial Function ◽

Bare Metal Stent ◽

Long Term Effects ◽

The Mean ◽

Sirolimus Eluting Stent ◽

Distal Site ◽

Quantitative Angiography ◽

D Dimer

Endothelial dysfunction is known to cause hypercoagulability. The long-term effects of sirolimus-eluting stent (SES) on endothelial function are not known. We evaluated endothelial function and local hypercoagulability more than six months following SES or bare metal stent (BMS) implantation. Forty-three patients treated six months earlier with a coronary stenting for isolated proximal left anterior descending (LAD) stenosis, with no evidence of restenosis, were studied. Sixteen patients had been stented with BMS, and 27 had been with SES. Changes in diameter at distal site of the stented LAD in response to intracoronary acetylcholine infusions (30μg/min) were assessed by quantitative angiography. We also measured plasma levels of prothrombin fragment F1+2 (F1+2) and D-dimer sampled in coronary sinus (CS) and sinus of Valsalva (V). The mean percent change in the diameter of the stented LAD was significantly more in the SES group than in the BMS group (−33.4±5.9 vs. −19.8±6.0%, p<0.05). The translesional F1+2 gradient [F1+2(CS) minus F1+2(V)] and D-dimer gradient were greater in the SES group than in the BMS group (0.52±0.68 vs. −0.10±0.29 nmol/l, p<0.05 and 0.22 ±0.38 vs. −0.12±0.35 μg/ml, p<0.05, respectively). An increased local coagulative response and more severe endothelial dysfunction were observed long term after SES implantation as compared to BMS. In the SES group, delay of endothelial regrowth might be associated with our findings.

Download Full-text

AB0577 ENDOTHELIAL DYSFUNCTION AND ATHEROSCLEROSIS IN SYSTEMIC SCLEROSIS: A MULTIPARAMETRIC ANALYSIS USING IMAGING TECHNIQUE AND LABORATORY MARKERS OF INFLAMMATION AND VASCULAR FUNCTION: SCLERODERMA CV RISK STUDY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5655 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1585.2-1585

Author(s):

N. Garg ◽

A. Syngle ◽

D. Gera ◽

S. Kaur

Keyword(s):

Cardiovascular Disease ◽

Systemic Sclerosis ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Vascular Function ◽

Disease Duration ◽

Atherosclerotic Cardiovascular Disease ◽

Accelerated Atherosclerosis ◽

Markers Of Inflammation ◽

Increased Risk

Background:Systemic sclerosis (SSc) patients have an increased risk for atherosclerotic cardiovascular disease (CVD), possibly mediated by inflammatory and fibrotic mechanisms1. However, pathogenesis of accelerated atherosclerosis in SSc remains to be elucidated. Endothelial dysfunction is the key initial event in atherosclerosis. Predictors for rapid evolution of cardiovascular complications would be highly desirable for CV risk stratification. This study aims to assess endothelial function and atherosclerosis in SSc, in context of markers of inflammation and vascular function in SSc patients.Objectives:To assess endothelial function and atherosclerosis in SSc in context of markers of inflammation and vascular function in SSc patients.Methods:A cross-sectional study was performed in 20 SSc patients meeting the 2013 European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) classification criteria and 18 healthy controls matched for age and sex. Flow-mediated dilatation (FMD) assessed by AngioDefender and CIMT measured ultrasonographically. Disease-specific measures included: Disease duration, Modified Rodnan Skin Score (mRSS), EUSTAR activity score in SSc. We also assayed markers of inflammation, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), proinflammatory cytokines (interleukin IL-1, IL-6, and IL-17), and endothelial dysfunction including lipids, serum nitrite and TBARS (marker of oxidative stress). Quality of life measured by Scleroderma Health Assessment Questionnaire (SHAQ).Results:FMD is significantly lower in SSc patients compared with controls (6.13±0.35% vs. 9.12±0.25%, p≤0.05). CIMT is significantly higher in SSc patients compared with controls (0.071±0.04cm vs. 0.035±0.02cm p≤0.05). Compared with controls, SSc patients had significantly (p≤0.05) elevated mRSS, EUSTAR score, ESR, CRP, IL-1, IL-6, IL-17, nitrite, TBARS and SHAQ whereas HDL levels are significantly reduced in SSc compared with controls (p≤0.05). In SSc, FMD inversely correlated with EUSTAR score, mRSS, IL-6 (Fig. 1A), serum nitrite (Fig. 1B), TBARS (Fig. 1C) and CIMT (Fig. 1D). CIMT positively correlated with age (Fig. 2A), disease duration, CRP (Fig. 2B) and IL-17 (Fig. 2C) and inversely correlated with HDL (Fig. 2D) (p< 0.05).Conclusion:In the present study, FMD and CIMT are impaired in SSc, indicating endothelial dysfunction and accelerated atherosclerosis, respectively. EUSTAR score, mRSS, IL-6, serum nitrite, CIMT and TBARS predicted endothelial dysfunction. Age, disease duration, CRP, IL-17, HDL and impaired FMD predicted accelerated atherosclerosis. SSc-related inflammatory mechanisms (IL-6, IL-17) and markers of vascular function (CRP, serum nitrite and TBARS) may all be involved in the development of vascular disease in SSc. Cytokine-triggered inflammation mediated by nitrite and TBARS is associated with endothelial dysfunction and accelerated atherosclerosis in SSc. These markers would possibly serve as predictors of endothelial dysfunction and atherosclerosis and more importantly therapeutic targets to prevent premature atherosclerosis and cardiovascular disease in SSc.References:[1]Pagkopoulou E, Poutakidou M, Garyfallos A, Kitas G, Dimitroulas T. Cardiovascular risk in systemic sclerosis: Micro- and Macro-vascular involvement. Indian Journal of Rheumatology 2017;12:S211-7.Acknowledgments:NoneDisclosure of Interests:None declared

Download Full-text

Repair of Protruding Bilateral Cleft Lip and Palate With Staged Premaxilla Setback Osteotomy, Cheiloplasty, and Palatoplasty in Trisomy 17p Patient: A Review of Syndromic Clinical Characteristic

The Cleft Palate-Craniofacial Journal ◽

10.1177/10556656211069820 ◽

2021 ◽

pp. 105566562110698

Author(s):

Kristaninta Bangun ◽

Jessica Halim ◽

Vika Tania

Keyword(s):

Cleft Lip ◽

Cleft Lip And Palate ◽

Surgical Techniques ◽

Chromosome 17 ◽

Long Term Effects ◽

Surgical Strategies ◽

Increased Risk ◽

The Cost

Chromosome 17 duplication is correlated with an increased risk of developmental delay, birth defects, and intellectual disability. Here, we reported a female patient with trisomy 17 on the whole short arm with bilateral complete cleft lip and palate (BCLP). This study will review the surgical strategies to reconstruct the protruding premaxillary segment, cleft lip, and palate in trisomy 17p patient. The patient had heterozygous pathogenic duplication of chromosomal region chr17:526-18777088 on almost the entire short arm of chromosome 17. Beside the commonly found features of trisomy 17p, the patient also presented with BCLP with a prominent premaxillary portion. Premaxillary setback surgery was first performed concomitantly with cheiloplasty. The ostectomy was performed posterior to the vomero-premaxillary suture (VPS). The premaxilla was firmly adhered to the lateral segment and the viability of philtral flap was not compromised. Two-flap palatoplasty with modified intravelar veloplasty (IVV) was performed 4 months after. Successful positioning of the premaxilla segment, satisfactory lip aesthetics, and vital palatal flap was obtained from premaxillary setback, primary cheiloplasty, and subsequent palatoplasty in our trisomy 17p patient presenting with BLCP. Postoperative premaxillary stability and patency of the philtral and palatal flap were achieved. Longer follow-up is needed to evaluate the long-term effects of our surgical techniques on inhibition of midfacial growth. However, the benefits that the patient received from the surgery in improving feeding capacity and facial appearance early in life outweigh the cost of possible maxillary retrusion.

Download Full-text

Second-Generation Consequences of Small-for-Dates Birth

PEDIATRICS ◽

10.1542/peds.84.2.343 ◽

1989 ◽

Vol 84 (2) ◽

pp. 343-347

Author(s):

Mark A. Klebanoff ◽

Olav Meirik ◽

Heinz W. Berendes

Keyword(s):

Confidence Interval ◽

Birth Outcomes ◽

Odds Ratio ◽

Intrauterine Growth Retardation ◽

Long Term Effects ◽

Intrauterine Growth ◽

Increased Risk ◽

Reported Study ◽

Increase In Risk

This is the first reported study of birth outcomes of a group of women whose own birth weights and gestational ages had been previously recorded. Births occurring from 1972 to 1983 among 1154 Swedish women, born from 1955 to 1965, were studied. Women who were themselves small for gestational age (SGA) at birth were at increased risk of giving birth to a SGA infant (odds ratio = 2.21, 95% confidence interval = 1.41, 3.48). Women who had been SGA had an even greater increase in risk of giving birth to a preterm infant (odds ratio = 2.96, 95% confidence interval = 1.47, 5.94). Women who were preterm at birth were not at increased risk of giving birth to either preterm (odds ratio = 0.65, 95% confidence interval = 0.15, 2.74) or SGA (odds ratio 1.21, 95% confidence interval = 0.62, 2.38) infants. It is concluded that the long-term effects of intrauterine growth retardation may extend to the next generation; women who had been SGA should be considered at increased risk to give birth to both growth-retarded and preterm infants.

Download Full-text

Maternal Overnutrition Induces Long-Term Cognitive Deficits across Several Generations

Nutrients ◽

10.3390/nu11010007 ◽

2018 ◽

Vol 11 (1) ◽

pp. 7 ◽

Cited By ~ 8

Author(s):

Gitalee Sarker ◽

Daria Peleg-Raibstein

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Cognitive Deficits ◽

Maternal Obesity ◽

Cognitive Impairments ◽

Long Term Effects ◽

Ample Evidence ◽

Increased Risk ◽

Maternal Overnutrition

Ample evidence from epidemiological studies has linked maternal obesity with metabolic disorders such as obesity, cardiovascular disease, and diabetes in the next generation. Recently, it was also shown that maternal obesity has long-term effects on the progeny’s central nervous system. However, very little is known regarding how maternal overnutrition may affect, in particular, the cognitive abilities of the offspring. We reported that first-generation offspring exposed to a maternal high-fat diet (MHFD) displayed age-dependent cognitive deficits. These deficits were associated with attenuations of amino acid levels in the medial prefrontal cortex and the hippocampus regions of MHFD offspring. Here, we tested the hypothesis that MHFD in mice may induce long-term cognitive impairments and neurochemical dysfunctions in the second and third generations. We found that MHFD led to cognitive disabilities and an altered response to a noncompetitive receptor antagonist of the N-Methyl-D-aspartic acid (NMDA) receptor in adult MHFD offspring in both second and third generations in a sex-specific manner. Our results suggest that maternal overnutrition leads to an increased risk of developing obesity in subsequent generations as well as to cognitive impairments, affecting learning and memory processes in adulthood. Furthermore, MHFD exposure may facilitate pathological brain aging which is not a consequence of obesity. Our findings shed light on the long-term effects of maternal overnutrition on the development of the central nervous system and the underlying mechanisms which these traits relate to disease predisposition.

Download Full-text

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

International Journal of Molecular Sciences ◽

10.3390/ijms19123942 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3942 ◽

Cited By ~ 6

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.

Download Full-text

Long-Term Overconsumption of Sugar Starting at Adolescence Produces Persistent Hyperactivity and Neurocognitive Deficits in Adulthood

Frontiers in Neuroscience ◽

10.3389/fnins.2021.670430 ◽

2021 ◽

Vol 15 ◽

Author(s):

Kate Beecher ◽

Ignatius Alvarez Cooper ◽

Joshua Wang ◽

Shaun B. Walters ◽

Fatemeh Chehrehasa ◽

...

Keyword(s):

Dietary Habits ◽

Hippocampal Neurogenesis ◽

Neurocognitive Deficits ◽

Long Term Effects ◽

Sugar Consumption ◽

Food And Beverages ◽

Increased Risk ◽

Newborn Neurons ◽

Dependent Learning

Sugar has become embedded in modern food and beverages. This has led to overconsumption of sugar in children, adolescents, and adults, with more than 60 countries consuming more than four times (>100 g/person/day) the WHO recommendations (25 g/person/day). Recent evidence suggests that obesity and impulsivity from poor dietary habits leads to further overconsumption of processed food and beverages. The long-term effects on cognitive processes and hyperactivity from sugar overconsumption, beginning at adolescence are not known. Using a well-validated mouse model of sugar consumption, we found that long-term sugar consumption, at a level that significantly augments weight gain, elicits an abnormal hyperlocomotor response to novelty and alters both episodic and spatial memory. Our results are similar to those reported in attention deficit and hyperactivity disorders. The deficits in hippocampal-dependent learning and memory were accompanied by altered hippocampal neurogenesis, with an overall decrease in the proliferation and differentiation of newborn neurons within the dentate gyrus. This suggests that long-term overconsumption of sugar, as that which occurs in the Western Diet might contribute to an increased risk of developing persistent hyperactivity and neurocognitive deficits in adulthood.

Download Full-text

Total Hip Replacement Provokes Endothelial Dysfunction

Angiology ◽

10.1177/0003319718774660 ◽

2018 ◽

Vol 69 (10) ◽

pp. 871-877 ◽

Cited By ~ 3

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.

Download Full-text

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00607.2020 ◽

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/

Download Full-text