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Impaired A2A adenosine receptor/nitric oxide/VEGF signaling pathway in fetal endothelium during late- and early-onset preeclampsia.

ABSTRACT: To investigate whether fetal endothelial cell proliferation and migration are modulated by the A2A adenosine receptor (A2AAR), nitric oxide (NO) and the vascular endothelial growth factor (VEGF) signaling pathway, we isolated human umbilical vein endothelial cells from normal pregnancy (n = 23), preterm delivery (n = 4), and late-onset (LOPE, n = 10) and early-onset preeclampsia (EOPE, n = 8). We used the non-selective adenosine receptor agonist (NECA) and the selective agonist (CGS-21680) and/or selective antagonist (ZM-241385) for A2AAR. Also, the nitric oxide synthase (NOS) inhibitor, L-NAME, was used in co-incubation with CGS-21680. Compared to normal pregnancy, EOPE exhibited low cell proliferation and migration associated with reduced expressions of A2AAR and VEGF and NO synthesis (i.e., total and phosphorylated serine(1177) endothelial NOS and nitrite formation). In contrast, LOPE exhibited the opposite behavior in all these markers compared to normal pregnancy or EOPE. Cell proliferation and migration were increased by CGS-21680 (or NECA) in all analyzed groups (EOPE>LOPE>normal pregnancy) compared to their respective basal conditions, an effect that was associated with high NO and VEGF synthesis and blocked by ZM-241385 with significantly different IC50 for each group (EOPE>LOPE>normal pregnancy). The differences seem independent of gestational age. L-NAME blocked the CGS-21680-mediated cell proliferation and migration in normal pregnancy and LOPE (IC50 = 36.2 ± 2.5 and 8.6 ± 2.2 nM, respectively) as well as the VEGF expression in normal pregnancy. Therefore, the A2AAR/NO/VEGF signaling pathway exhibits a pro-angiogenic effect in normal pregnancies and LOPE, whereas impairment in this pathway seems related to the reduced angiogenic capacity of the fetal endothelium in EOPE.

SUBMITTER: Escudero C

PROVIDER: S-EPMC3646121 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Impaired A2A adenosine receptor/nitric oxide/VEGF signaling pathway in fetal endothelium during late- and early-onset preeclampsia.

Escudero Carlos C Bertoglia Patricio P Hernadez Myriam M Celis Cristian C Gonzalez Marcelo M Aguayo Claudio C Acurio Jesenia J

Purinergic signalling 20121121 2

To investigate whether fetal endothelial cell proliferation and migration are modulated by the A2A adenosine receptor (A2AAR), nitric oxide (NO) and the vascular endothelial growth factor (VEGF) signaling pathway, we isolated human umbilical vein endothelial cells from normal pregnancy (n = 23), preterm delivery (n = 4), and late-onset (LOPE, n = 10) and early-onset preeclampsia (EOPE, n = 8). We used the non-selective adenosine receptor agonist (NECA) and the selective agonist (CGS-21680) and/o ...[more]

PMID: 23179048

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Project description:BackgroundA well-known blood biomarker (soluble fms-like tyrosinase-1 [sFLT-1]) for preeclampsia, i.e., a pregnancy disorder, was found to predict severe COVID-19, including in males. True biomarker may be masked by more-abrupt changes related to endothelial instead of placental dysfunction. This study aimed to identify blood biomarkers that represent maternal-fetal interface tissues for predicting preeclampsia but not COVID-19 infection.MethodsThe surrogate transcriptome of tissues was determined by that in maternal blood, utilizing four datasets (n = 1354) which were collected before the COVID-19 pandemic. Applying machine learning, a preeclampsia prediction model was chosen between those using blood transcriptome (differentially expressed genes [DEGs]) and the blood-derived surrogate for tissues. We selected the best predictive model by the area under the receiver operating characteristic (AUROC) using a dataset for developing the model, and well-replicated in datasets both with and without an intervention. To identify eligible blood biomarkers that predicted any-onset preeclampsia from the datasets but that were not positive in the COVID-19 dataset (n = 47), we compared several methods of predictor discovery: (1) the best prediction model; (2) gene sets of standard pipelines; and (3) a validated gene set for predicting any-onset preeclampsia during the pandemic (n = 404). We chose the most predictive biomarkers from the best method with the significantly largest number of discoveries by a permutation test. The biological relevance was justified by exploring and reanalyzing low- and high-level, multiomics information.ResultsA prediction model using the surrogates developed for predicting any-onset preeclampsia (AUROC of 0.85, 95 % confidence interval [CI] 0.77 to 0.93) was the only that was well-replicated in an independent dataset with no intervention. No model was well-replicated in datasets with a vitamin D intervention. None of the blood biomarkers with high weights in the best model overlapped with blood DEGs. Blood biomarkers were transcripts of integrin-α5 (ITGA5), interferon regulatory factor-6 (IRF6), and P2X purinoreceptor-7 (P2RX7) from the prediction model, which was the only method that significantly discovered eligible blood biomarkers (n = 3/100 combinations, 3.0 %; P =.036). Most of the predicted events (73.70 %) among any-onset preeclampsia were cluster A as defined by ITGA5 (Z-score ≥ 1.1), but were only a minority (6.34 %) among positives in the COVID-19 dataset. The remaining were predicted events (26.30 %) among any-onset preeclampsia or those among COVID-19 infection (93.66 %) if IRF6 Z-score was ≥-0.73 (clusters B and C), in which none was the predicted events among either late-onset preeclampsia (LOPE) or COVID-19 infection if P2RX7 Z-score was <0.13 (cluster C). Greater proportions of predicted events among LOPE were cluster A (82.85 % vs 70.53 %) compared to early-onset preeclampsia (EOPE). The biological relevance by multiomics information explained the biomarker mechanism, polymicrobial infection in any-onset preeclampsia by ITGA5, viral co-infection in EOPE by ITGA5-IRF6, a shared prediction with COVID-19 infection by ITGA5-IRF6-P2RX7, and non-replicability in datasets with a vitamin D intervention by ITGA5.ConclusionsIn a model that predicts preeclampsia but not COVID-19 infection, the important predictors were genes in maternal blood that were not extremely expressed, including the proposed blood biomarkers. The predictive performance and biological relevance should be validated in future experiments.

Project description:A(2A) adenosine receptor (A(2A)AR) has been shown to suppress superoxide generation in leukocytes via the cAMP-protein kinase A (PKA) pathway. However, no study has yet explored the role of A(2A)AR in relation to NADPH oxidase in murine tracheas in vitro, which may lead to altered smooth muscle relaxation in asthma. Therefore, the present study evaluated the effects of A(2A)AR deficiency on the NADPH oxidase pathway in tracheas of A(2A) wild-type (WT) and A(2A) knockout (KO) mice. A(2A)WT mice were sensitized with ovalbumin (30 microg i.p.) on days 1 and 6, followed by 5% ovalbumin aerosol challenge on days 11, 12, and 13. A(2A)AR (gene and protein expression), cAMP, and phosphorylated PKA (p-PKA) levels were decreased in A(2A)WT sensitized mice compared with controls. A(2A)KO mice also showed decreased cAMP and p-PKA levels. A(2A)WT sensitized and A(2A)KO control mice had increased gene and protein expression of NADPH oxidase subunits (p47phox and gp91phox) compared with the controls. Tracheal relaxation to specific A(2A)AR agonist, 4-[2-[[6-amino-9-(N-ethyl-beta-d-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid hydrochloride (CGS 21680), decreased in A(2A)WT sensitized mice compared with the controls, although it was absent in A(2A)KO mice. Pretreatment with NADPH oxidase inhibitors apocyanin/diphenyliodonium reversed the attenuated relaxation to CGS 21680 in A(2A)WT sensitized tracheas, whereas specific PKA inhibitor (9S,10S,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i] [1,6]benzodiazocine-10-carboxylic acid hexyl ester (KT 5720) blocked CGS 21680-induced relaxation. Tracheal reactive oxygen species (ROS) generation was also increased in A(2A)WT sensitized and A(2A)KO control mice compared with the controls. In conclusion, this study shows that A(2A)AR deficiency causes increased NADPH oxidase activation leading to decreased tracheal relaxation via altered cAMP-PKA signaling and ROS generation.

Project description:Hypertension in pregnancy is the leading cause of morbidity and mortality in pregnancy, affecting up to 10% of all gestations1. Hypertensive disorders of pregnancy include chronic hypertension, gestational hypertension, eclampsia and pre-eclampsia, all of which increase the risk of complications in both mothers and babies during gestation. Preeclampsia, in particular, is characterised by the new-onset of gestational hypertension in the presence of proteinuria or other organ damage. It affects 5-7% of pregnancies and causes approximately 76,000 maternal deaths and 500,000 foetal deaths worldwide each year2. The classification of preeclampsia has been evolving over the last decade. In 2013, American College of Obstetricians and Gynecologists (ACOG) and International Society for the Study of Hypertension in Pregnancy (ISSHP) in the absence of proteinuria included other symptoms/features including liver dysfunction, thrombocytopenia, cerebrovascular events or foetal growth restriction (FGR) in the diagnosis of preeclampsia 1,3,4. Despite the fact that preeclampsia is a multifactorial and heterogeneous disorder, it is now widely accepted that preeclampsia is stratified depending on the time of onset into: i) early-onset PE (EOPE) manifested before 34 weeks of gestation, and ii) late-onset PE (LOPE) manifested from 34 weeks of gestation. Although EOPE and LOPE share the same diagnostic criteria, these two phenotypes of preeclampsia lead to different outcomes. EOPE is commonly associated with FGR, abnormal uterine artery Doppler often leading to preterm birth and higher risk of post-pregnancy morbidities5,6. On the other hand, LOPE appears to be a less severe disorder, often with normal or slightly increased uterine resistance index and a low rate of FGR6,7. Distinct delineation between EOPE and LOPE is still not well understood, with most patients with preeclampsia presenting elements of both pathologies proposing a clinical spectrum for preeclampsia. The lack of untargeted discovery studies involving ‘omics’ analyses has impeded understanding of the molecular differences between these two phenotypes of preeclampsia. Notably, a study from 20058 utilised a proteomics approach using urine samples from a cohort of pregnant women with EOPE and healthy controls, however the differences between EOPE and LOPE were not elucidated. Another more recent bioinformatics study, identified overlapping pathogenic mechanisms between preeclampsia, hypertension and heart disease but could not stratify between EOPE and LOPE due to underreported of data related to individual phenotypes9. In this study, we conducted an unbiased, comprehensive proteomics investigation using plasma samples collected from patients with EOPE (n=17) and LOPE (n=11), compared with age- and BMI-matched normotensive controls (n=18). The use of plasma samples is able to better reflect the pathogenesis of EOPE and LOPE as systemic conditions centred by widespread endothelial dysfunction.

Dataset Information

Impaired A2A adenosine receptor/nitric oxide/VEGF signaling pathway in fetal endothelium during late- and early-onset preeclampsia.

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Impaired A2A adenosine receptor/nitric oxide/VEGF signaling pathway in fetal endothelium during late- and early-onset preeclampsia.

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