Current Vascular Pharmacology - Volume 19, Issue 2, 2021

The incidence of obesity is rising rapidly worldwide with the consequence that more women are entering pregnancy overweight or obese. This leads to an increased incidence of clinical complications during pregnancy and of poor obstetric outcomes. The offspring of obese pregnancies are often macrosomic at birth although there is also a subset of the progeny that are growth-restricted at term. Maternal obesity during pregnancy is also associated with cardiovascular, metabolic and endocrine dysfunction in the offspring later in life. As the interface between the mother and fetus, the placenta has a central role in programming intrauterine development and is known to adapt its phenotype in response to environmental conditions such as maternal undernutrition and hypoxia. However, less is known about placental function in the abnormal metabolic and endocrine environment associated with maternal obesity during pregnancy. This review discusses the placental consequences of maternal obesity induced either naturally or experimentally by increasing maternal nutritional intake and/or changing the dietary composition. It takes a comparative, multi-species approach and focusses on placental size, morphology, nutrient transport, metabolism and endocrine function during the later stages of obese pregnancy. It also examines the interventions that have been made during pregnancy in an attempt to alleviate the more adverse impacts of maternal obesity on placental phenotype. The review highlights the potential role of adaptations in placental phenotype as a contributory factor to the pregnancy complications and changes in fetal growth and development that are associated with maternal obesity.

Healthy lifestyle habits spanning from preconception to postpartum are considered as a major safeguard for achieving successful pregnancies and for the prevention of gestational diseases. Among preconception priorities established by the World Health Organization (WHO) are healthy diet and nutrition, weight management, physical activity, planned pregnancy and physical, mental and psychosocial health. Most studies covering the topic of healthy pregnancies focus on maternal diet because obesity increases the risks for adverse perinatal outcomes, including gestational diabetes mellitus, large for gestational age newborns, or preeclampsia. Thus, foods rich in vegetables, essential and polyunsaturated fats and fibre-rich carbohydrates should be promoted especially in overweight, obese or diabetic women. An adequate intake of micronutrients (e.g. iron, calcium, folate, vitamin D and carotenoids) is also crucial to support pregnancy and breastfeeding. Moderate physical activity throughout pregnancy improves muscle tone and function, besides decreasing the risk of preeclampsia, gestational diabesity (i.e. diabetes associated with obesity) and postpartum overweight. Intervention studies claim that an average of 30 min of exercise/day contributes to long-term benefits for maternal overall health and wellbeing. Other factors such as microbiome modulation, behavioural strategies (e.g. smoking cessation, anxiety/stress reduction and sleep quality), maternal genetics and age, social class and education might also influence the maternal quality of life. These factors contribute to ensure a healthy pregnancy, or at least to reduce the risk of adverse maternal and foetal outcomes during pregnancy and later in life.

Normal pregnancy is associated with increased insulin resistance as a metabolic adaptation to the nutritional demands of the placenta and fetus, and this is amplified in obese mothers. Insulin resistance is normally compensated for by an adaptive increase in pancreatic β-cell mass together with enhanced glucose-stimulated insulin release. Placentally-derived hormones and growth factors are central to the altered pancreatic morphology and function. A failure of β-cells to undergo adaptive change after the first trimester has been linked with gestational diabetes. In the pregnant mouse, an increase in β-cell replication contributes to a 2-3-fold increase in mass peaking in late gestation, depending on the proliferation of existing β-cells, the differentiation of resident progenitor β-cells, or islet cell transdifferentiation. Using mouse models and human studies placenta- and islet of Langerhans-derived molecules have been identified that are likely to contribute to the metabolic adaptations to pregnancy and whose physiology is altered in the obese, glucose-intolerant mother. Maternal obesity during pregnancy can create a pro-inflammatory environment that can disrupt the response of the β-cells to the endocrine signals of pregnancy and limit the adaptive changes in β-cell mass and function, resulting in an increased risk of gestational diabetes.

Obesity and Gestational Diabetes Mellitus (GDM) are the most frequent pathologies affecting mothers and offspring during pregnancy. Both conditions have shown a sustained increase in their prevalence in recent years, and they worsen the outcome of pregnancy and the long-term health of mothers. Obesity increases the risk of GDM and pre-eclampsia during pregnancy and elevates the risk of developing metabolic syndrome in later life. Offspring of obese mothers have an increased risk of obstetric morbidity and mortality and, consistent with the developmental origins of health and disease, a long term risk of childhood obesity and metabolic dysfunction. On the other hand, GDM also increases the risk of pre-eclampsia, caesarean section, and up to 50% of women will develop type 2 diabetes later in life. From a fetal point of view, it increases the risk of macrosomia, large-for-gestational-age fetuses, shoulder dystocia and birth trauma. The insulin resistance and inflammatory mediators released by a hypoxic trophoblast are mainly responsible for the poor pregnancy outcome in obese or GDM patients. The adequate management of both pathologies includes modifications in the diet and physical activity. Drug therapy should be considered when medical nutrition therapy and moderate physical activity fail to achieve treatment goals. The antenatal prediction of macrosomia is a challenge for physicians. The timing and the route of delivery should consider adequate metabolic control, gestational age, and optimal conditions for a vaginal birth. The best management of these pathologies includes pre-conception planning to reduce the risks during pregnancy and improve the quality of life of these patients.

Over the past 20 years, the prevalence of obesity has risen dramatically worldwide, with an increase in occurrence among women in their reproductive age. Obesity during pregnancy is associated with significantly increased maternal and fetal morbidity and mortality. In addition to the short-term adverse health outcomes, both mother and the child are prone to develop cardiovascular, metabolic and neurological disorders. Although associations between obesity during pregnancy and adverse maternalfetal health outcomes are clear, the complex molecular mechanisms underlying maternal obesity remain largely unknown. This review describes multimeric self-assembling protein complexes, namely inflammasomes, as potential molecular targets in the pathophysiology of maternal obesity. Inflammasomes are implicated in both normal physiological and in pathophysiological processes that occur in response to an inflammatory milieu throughout gestation. This review highlights the current knowledge of inflammasome expression and its activity in pregnancies affected by maternal obesity. Key discussions in defining pharmacological inhibition of upstream as well as downstream targets of the inflammasome signaling cascade; and the inflammasome platform, as a potential therapeutic strategy in attenuating the pathophysiology underpinning inflammatory component in maternal obesity are presented herein.

Obesity and gestational diabetes mellitus (GDM) are becoming more common among pregnant women worldwide and are individually associated with a number of placenta-mediated obstetric complications, including preeclampsia, macrosomia, intrauterine growth restriction and stillbirth. The placenta serves several functions throughout pregnancy and is the main exchange site for the transfer of nutrients and gas from mother to fetus. In pregnancies complicated by maternal obesity or GDM, the placenta is exposed to environmental changes, such as increased inflammation and oxidative stress, dyslipidemia, and altered hormone levels. These changes can affect placental development and function and lead to abnormal fetal growth and development as well as metabolic and cardiovascular abnormalities in the offspring. This review aims to summarize current knowledge on the effects of obesity and GDM on placental development and function. Understanding these processes is key in developing therapeutic interventions with the goal of mitigating these effects and preventing future cardiovascular and metabolic pathology in subsequent generations.

Obesity is a worldwide public health problem, affecting at least one-third of pregnant women. One of the main problems of obesity during pregnancy is the resulting high rate of cesarean section. The leading cause of this higher frequency of cesarean sections in obese women, compared with that in nonobese women, is an altered myometrial function that leads to lower frequency and potency of contractions. In this article, the disruptions of myometrial myocytes were reviewed in obese women during pregnancy that may explain the dysfunctional labor. The myometrium of obese women exhibited lower expression of connexin43, a lower function of the oxytocin receptor, and higher activity of the potassium channels. Adipokines, such as leptin, visfatin, and apelin, whose concentrations are higher in obese women, decreased myometrial contractility, perhaps by inhibiting the myometrial RhoA/ROCK pathway. The characteristically higher cholesterol levels of obese women alter myometrial myocyte cell membranes, especially the caveolae, inhibiting oxytocin receptor function, and increasing the K+ channel activity. All these changes in the myometrial cells or their environment decrease myometrial contractility, at least partially explaining the higher rate of cesarean of sections in obese women.

Background and Aim: The endoplasmic reticulum (ER) stress response and the unfolded protein response (UPR) are essential cellular mechanisms to ensure the proper functioning of ER in adverse conditions. However, activation of these pathways has also been associated with insulin resistance and cell death in pathological conditions such as diabetes mellitus. In the present study, we investigated whether stromal cell-derived factor 2 (SDF2)—an ER stress-responsive factor—is related to ER response in placental cells exposed to maternal gestational diabetes mellitus (GDM) or to a hyperglycaemic in vitro condition. Objective: The study aimed to investigate the role of SDF2 in BeWo cells , a trophoblast cell line originating from choriocarcinoma , and in placental tissue under hyperglycaemic conditions. Methods: Protein levels of SDF2 and UPR factors, glucose-related protein 78 (GRP78) and eukaryotic initiation factor 2 alpha (elF2 alpha) were evaluated in the placentae of pregnant women diagnosed with GDM and treated by diet-control (insulin was added when necessary). The mRNA expression of SDF2 and UPR factors CHOP and sXBP1 were assessed in cultured BeWo cells challenged with glucose and treated with or without insulin. Results: SDF2 expression was increased in the placentae of GDM women treated with diet. However, its values were similar to those of normoglycemic controls when the GDM women were treated with insulin and diet. BeWo cells cultured with high glucose and insulin showed decreased SDF2 expression, while high glucose increased CHOP and sXBP1 expression, which was then significantly reverted with insulin treatment. Conclusion: Our findings extend the understanding of ER stress and SDF2 expression in placentae exposed to hyperglycaemia, highlighting the relevance of insulin in reducing the levels of ER stress factors in placental cells. Understanding the effect of ER stress partners such as SDF2 on signalling pathways involved in gestation, complicated by hyperglycaemia, is pivotal for basic biomedical research and may lead to new therapeutic possibilities.

Sleep is essential to and an integral part of life and when lacking or disrupted, a multitude of mental and physical pathologies ensue, including cardiovascular (CV) disease, which increases health care costs. Several prospective studies and meta-analyses show that insomnia, short (<7h) or long (>9h) sleep and other sleep disorders are associated with an increased risk of hypertension, metabolic syndrome, myocardial infarction, heart failure, arrhythmias, CV disease risk and/or mortality. The mechanisms by which insomnia and other sleep disorders lead to increased CV risk may encompass inflammatory, immunological, neuro-autonomic, endocrinological, genetic and microbiome perturbations. Guidelines are emerging that recommend a target of >7 h of sleep for all adults >18 years for optimal CV health. Treatment of sleep disorders includes cognitive-behavioral therapy considered the mainstay of non-pharmacologic management of chronic insomnia, and drug treatment with benzodiazepine receptor agonists binding to gamma aminobutyric acid type A (benzodiazepine and non-benzodiazepine agents) and some antidepressants. However, observational studies and meta-analyses indicate an increased mortality risk of anxiolytics and hypnotics, although bias may be involved due to confounding and high heterogeneity in these studies. Nevertheless, it seems that the risk incurred by the non-benzodiazepine hypnotic agents (Z drugs) may be relatively less than the risk of anxiolytics, with evidence indicating that at least one of these agents, zolpidem, may even confer a lower risk of mortality in adjusted models. All these issues are herein reviewed.

Type 2 diabetes mellitus (T2DM) is a rapidly evolving global health issue associated with a markedly increased risk of cardiovascular (CV) morbidity and mortality. The hyperglycaemic milieu contributes to the development of CV complications via several pathological pathways, leading to increased arterial stiffness (AS), that can be considered as a predictor of CV events in patients with diabetes. The measurement of AS is increasingly used for the clinical assessment of patients. Several methodologies were used in extensive population studies to assess AS; the most commonly used is the pulse wave velocity (PWV). The cardio-ankle vascular index (CAVI) was developed to measure AS; it is not affected by blood pressure at the time of measurement and shows stable values in healthy persons for years. There are several potential pharmacological and non-pharmacological interventions aiming to reduce AS. Recent evidence from clinical trials suggests that newer antidiabetic drugs do not only exert glycaemic-lowering properties but also decrease CV risk. In this context, sodium glucose cotransporter- 2 inhibitors (SGLT2i) ( empagliflozin, canagliflozin and dapagliflozin) significantly reduced the risk of CV and all-cause mortality (only EMPA-REG OUTCOME study) and hospitalization for heart failure in patients with T2DM with established CV disease and/or with CV risk factors. Improved endothelial function and AS probably represents one of the mechanisms by which these drugs exert their beneficial effects. The present review aimed both to describe the association between AS and T2DM and to discuss the effectiveness of SGLT2i on vascular endothelial dysfunction and AS.