Maternal supraphysiological hypercholesterolemia associates with endothelial dysfunction of the placental microvasculature

Maternal physiological or supraphysiological hypercholesterolemia (MPH, MSPH) occurs during pregnancy. MSPH is associated with foetal endothelial dysfunction and atherosclerosis. However, the potential effects of MSPH on placental microvasculature are unknown. The aim of this study was to determine whether MSPH alters endothelial function in the placental microvasculature both ex vivo in venules and arterioles from the placental villi and in vitro in primary cultures of placental microvascular endothelial cells (hPMEC). Total cholesterol < 280 mg/dL indicated MPH, and total cholesterol ≥280 mg/dL indicated MSPH. The maximal relaxation to histamine, calcitonin gene-related peptide and adenosine was reduced in MSPH venule and arteriole rings. In hPMEC from MSPH placentas, nitric oxide synthase (NOS) activity and L-arginine transport were reduced without changes in arginase activity or the protein levels of endothelial NOS (eNOS), human cationic amino acid 1 (hCAT-1), hCAT-2A/B or arginase II compared with hPMEC from MPH placentas. In addition, it was shown that adenosine acts as a vasodilator of the placental microvasculature and that NOS is active in hPMEC. We conclude that MSPH alters placental microvascular endothelial function via a NOS/L-arginine imbalance. This work also reinforces the concept that placental endothelial cells from the macro- and microvasculature respond differentially to the same pathological condition.FONDECYT 1150344, 115037

Role of platelet-derived growth factor c on endothelial dysfunction in cardiovascular diseases

Loss of endothelial function is a common feature to all cardiovascular diseases (CVDs). One of the risk factors associated with the development of CVDs is the hyperglycaemia that occurs in patients with metabolic disorders such as Type 1 and Type 2 diabetes mellitus. Hyperglycaemia causes endothelial dysfunction through increased production of reactive oxygen species (ROS) from different cellular sources leading to oxidative stress. Vascular endothelial growth factor (VEGF) is essential in the stimulation and maintenance of endothelial functional aspects and, although it can mitigate the impact of ROS, VEGF-mediated signalling is partially inhibited in diabetes mellitus. The search for therapeutic strategies that preserve, protect and improve the functions of the endothelium is of great relevance in the investigation of CVDs associated with hyperglycaemia. Platelet-derived growth factor C (PDGF-C) is a peptide with angiogenic properties, independent of VEGF, that stimulates angiogenesis and revascularization of ischemic tissue. In a diabetic mouse model, PDGF-C stimulates mature endothelial cell migration, angiogenesis, endothelial progenitor cell mobilization, and increased neovascularization, and protects blood vessels in a retinal degeneration model activating anti-apoptosis and proliferation signalling pathways in endothelial cells. This review summarizes the information on the damage that high D-glucose causes on endothelial function and the beneficial effects that PDGF-CC could exert in this condition

SARS- CoV-2 infection and oxidative stress in early-onset preeclampsia

SARS-CoV-2 causes coronavirus disease 2019 (COVID-19) also in pregnant women. Infection in pregnancy leads to maternal and placental functional alterations. Pregnant women with vascular defects such as preeclampsia show high susceptibility to SARS-CoV-2 infection by undefined mechanisms. Pregnant women infected with SARS-CoV-2 show higher rates of preterm birth and caesarean delivery, and their placentas show signs of vasculopathy and inflammation. It is still unclear whether the foetus is affected by the maternal infection with this virus and whether maternal infection associates with postnatal affections. The SARS-CoV-2 infection causes oxidative stress and activation of the immune system leading to cytokine storm and next tissue damage as seen in the lung. The angiotensin-converting-enzyme 2 expression is determinant for these alterations in the lung. Since this enzyme is expressed in the human placenta, SARS-CoV-2 could infect the placenta tissue, although reported to be of low frequency compared with maternal lung tissue. Early-onset preeclampsia (eoPE) shows higher expression of ADAM17 (a disintegrin and metalloproteinase 17) causing an imbalanced renin-angiotensin system and endothelial dysfunction. A similar mechanism seems to potentially account for SARS-CoV-2 infection. This review highlights the potentially common characteristics of pregnant women with eoPE with those with COVID-19. A better understanding of the mechanisms of SARS-CoV-2 infection and its impact on the placenta function is determinant since eoPE/COVID-19 association may result in maternal metabolic alterations that might lead to a potential worsening of the foetal programming of diseases in the neonate, young, and adult

Using Machine Learning to Predict Complications in Pregnancy:A Systematic Review

Introduction: Artificial intelligence is widely used in medical field, and machine learning has been increasingly used in health care, prediction, and diagnosis and as a method of determining priority. Machine learning methods have been features of several tools in the fields of obstetrics and childcare. This present review aims to summarize the machine learning techniques to predict perinatal complications. Objective: To identify the applicability and performance of machine learning methods used to identify pregnancy complications. Methods: A total of 98 articles were obtained with the keywords “machine learning,” “deep learning,” “artificial intelligence,” and accordingly as they related to perinatal complications (“complications in pregnancy,” “pregnancy complications”) from three scientific databases: PubMed, Scopus, and Web of Science. These were managed on the Mendeley platform and classified using the PRISMA method. Results: A total of 31 articles were selected after elimination according to inclusion and exclusion criteria. The features used to predict perinatal complications were primarily electronic medical records (48%), medical images (29%), and biological markers (19%), while 4% were based on other types of features, such as sensors and fetal heart rate. The main perinatal complications considered in the application of machine learning thus far are pre-eclampsia and prematurity. In the 31 studies, a total of sixteen complications were predicted. The main precision metric used is the AUC. The machine learning methods with the best results were the prediction of prematurity from medical images using the support vector machine technique, with an accuracy of 95.7%, and the prediction of neonatal mortality with the XGBoost technique, with 99.7% accuracy. Conclusion: It is important to continue promoting this area of research and promote solutions with multicenter clinical applicability through machine learning to reduce perinatal complications. This systematic review contributes significantly to the specialized literature on artificial intelligence and women’s health

Is a low level of free thyroxine in the maternal circulation associated with altered endothelial function in gestational diabetes?

Synthesis of thyroid hormones, thyroxine (T4) and tri-iodothyronine (T3), in the human fetus starts from 17 to 19th weeks of gestation. Despite the majority of normal pregnant women reaching adequate levels of circulating thyroid hormones, in some cases, women with normal pregnancies have low level of free T4 during first trimester of pregnancy, suggesting that T4 action may be compromised in those women and their fetuses. In addition, pathological low levels of thyroid hormones are detected in isolated maternal hypothyroxemia (IMH) and clinical hypothyroidism. Nevertheless, human placenta regulates T3/T4 concentration in the fetal circulation by modulating the expression and activity of both thyroid hormone transporters (THT) and deiodinases. Then, placenta can control the availability of T3/T4 in the feto-placental circulation, and therefore may generate an adaptive response in cases where the mother courses with low levels of T4. In addition, T3/T4 might control vascular response in the placenta, in particularly endothelial cells may induce the synthesis and release of vasodilators such as nitric oxide (NO) or vasoconstrictors such as endothelin-1 mediated by these hormones. On the other hand, low levels of T4 have been associated with increase in gestational diabetes (GD) markers. Since GD is associated with impaired placental vascular function characterized by increased NO synthesis in placental arteries and veins, as well as elevated placental angiogenesis, it is unknown whether reduced T4 level at the maternal circulation could result in an altered placental endothelial function during GD. In this review, we analyze available information regarding thyroid hormones and endothelial dysfunction in GD; and propose that low maternal levels of T4 observed in GD may be compensated by increased placental availability of T3/T4 via elevation in the activity of THT and/or reduction in deiodinases in the feto-placental circulation

Extracellular vesicle interactions with the external and internal exposome in mediating carcinogenesis

The influence of environmental factors on an individual, from conception onwards, is defined as the exposome. It can be categorized into the external exposome, which includes external factors such as air pollution, chemical contaminants, and diet, and the internal exposome, which is unique to an individual, and involves age, physiology, and their genetic profile. The effect of external exposures on the internal exposome, or genetic profile, can be determined through omics analyses. However, this is often compromised due to low sample quantity and cost. Therefore, identification of other factors that can provide an insight into the cellular profile of an individual, provides an exciting avenue, and an emerging field is that of extracellular vesicles (EVs). Recently, our understanding of how cells can communicate with each other has shifted to recognise the role of EVs. EVs are secreted by all living cells, and have been identified in all biological fluids studied so far. They transport bioactive molecules (e.g., proteins, miRNAs, and DNA), and their release can be regulated by the cellular microenvironment. Analysis of EVs in respond to environmental factors might provide novel insights into the role of tumour EVs in carcinogenesis. Not only will EVs give some insight into the tumour cells themselves but they will also provide a better understanding of how cells communicate with one another, contributing to cancer progression. Moreover, characterising the content and functions of tumour-derived EVs has the potential to overcome the current challenges to improve cancer patient outcomes. For example, the identification of EVs targets for therapeutic interventions and tumour EVs biomarkers could facilitate the development of early screening for several cancers. The aim of this review, thus, is to discuss the overall role of EVs in response to the various external and internal signals in cancer. We will specifically highlight the biogenesis, secretion, and content of EVs in response to oncogenic transformation and metabolic regulators in cancer

Cross Talk between Adipose Tissue and Placenta in Obese and Gestational Diabetes Mellitus Pregnancies via Exosomes

Obesity is an important public health issue worldwide, where it is commonly associated with the development of metabolic disorders, especially insulin resistance (IR). Maternal obesity is associated with an increased risk of pregnancy complications, especially gestational diabetes mellitus (GDM). Metabolism is a vital process for energy production and the maintenance of essential cellular functions. Excess energy storage is predominantly regulated by the adipose tissue. Primarily made up of adipocytes, adipose tissue acts as the body’s major energy reservoir. The role of adipose tissue, however, is not restricted to a “bag of fat.” The adipose tissue is an endocrine organ, secreting various adipokines, enzymes, growth factors, and hormones that take part in glucose and lipid metabolism. In obesity, the greater portion of the adipose tissue comprises fat, and there is increased pro-inflammatory cytokine secretion, macrophage infiltration, and reduced insulin sensitivity. Obesity contributes to systemic IR and its associated metabolic complications. Similar to adipose tissue, the placenta is also an endocrine organ. During pregnancy, the placenta secretes various molecules to maintain pregnancy physiology. In addition, the placenta plays an important role in metabolism and exchange of nutrients between mother and fetus. Inflammation at the placenta may contribute to the severity of maternal IR and her likelihood of developing GDM and may also mediate the adverse consequences of obesity and GDM on the fetus. Interestingly, studies on maternal insulin sensitivity and secretion of placental hormones have not shown a positive correlation between these phenomena. Recently, a great interest in the field of extracellular vesicles (EVs) has been observed in the literature. EVs are produced by a wide range of cells and are present in all biological fluids. EVs are involved in cell-to-cell communication. Recent evidence points to an association between adipose tissue-derived EVs and metabolic syndrome in obesity. In this review, we will discuss the changes in human placenta and adipose tissue in GDM and obesity and summarize the findings regarding the role of adipose tissue and placenta-derived EVs, with an emphasis on exosomes in obesity, and the contribution of obesity to the development of GDM