Delia I. Chiarello

Adenosine and preeclampsia

Adenosine is an endogenous nucleoside with pleiotropic effects in different physiological processes including circulation, renal blood flow, immune function, or glucose homeostasis. Changes in adenosine membrane transporters, adenosine receptors, and corresponding intracellular signalling network associate with development of pathologies of pregnancy, including preeclampsia. Preeclampsia is a cause of maternal and perinatal morbidity and mortality affecting 3-5% of pregnancies. Since the proposed mechanisms of preeclampsia development include adenosine-dependent biological effects, adenosine membrane transporters and receptors, and the associated signalling mechanisms might play a role in the pathophysiology of preeclampsia. Preeclampsia associates with increased adenosine concentration in the maternal blood and placental tissue, likely due to local hypoxia and ischemia (although not directly demonstrated), microthrombosis, increased catecholamine release, and platelet activation. In addition, abnormal expression and function of equilibrative nucleoside transporters is described in foetoplacental tissues from preeclampsia; however, the role of adenosine receptors in the aetiology of this disease is not well understood. Adenosine receptors activation may be related to abnormal trophoblast invasion, angiogenesis, and ischemia/reperfusion mechanisms in the placenta from preeclampsia. These mechanisms may explain only a low fraction of the associated abnormal transformation of spiral arteries in preeclampsia, triggering cellular stress and inflammatory mediators release from the placenta to the maternal circulation. Although increased adenosine concentration in preeclampsia may be a compensatory or adaptive mechanism favouring placental angiogenesis, a poor angiogenic state is found in preeclampsia. Thus, preeclampsia-associated complications might affect the cell response to adenosine due to altered expression and activity of adenosine receptors, membrane transporters, or cell signalling mechanisms. This review summarizes the evidence available on the potential involvement of the adenosine in the clinical, pathophysiology, and therapeutic features of preeclampsia.

Insulin Is a Key Modulator of Fetoplacental Endothelium Metabolic Disturbances in Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is a disease of the mother that associates with altered fetoplacental vascular function. GDM-associated maternal hyperglycaemia result in fetal hyperglycaemia, a condition that leads to fetal hyperinsulinemia and altered L-arginine transport and synthesis of nitric oxide, i.e., endothelial dysfunction. These alterations in the fetoplacental endothelial function are present in women with GDM that were under diet or insulin therapy. Since these women and their newborn show normal glycaemia at term, other factors or conditions could be altered and/or not resolved by restoring normal level of circulating D-glucose. GDM associates with metabolic disturbances, such as abnormal handling of the locally released vasodilator adenosine, and biosynthesis and metabolism of cholesterol lipoproteins, or metabolic diseases resulting in endoplasmic reticulum stress and altered angiogenesis. Insulin acts as a potent modulator of all these phenomena under normal conditions as reported in primary cultures of cells obtained from the human placenta; however, GDM and the role of insulin regarding these alterations in this disease are poorly understood. This review focuses on the potential link between insulin and endoplasmic reticulum stress, hypercholesterolemia, and angiogenesis in GDM in the human fetoplacental vasculature. Based in reports in primary culture placental endothelium we propose that insulin is a factor restoring endothelial function in GDM by reversing ERS, hypercholesterolaemia and angiogenesis to a physiological state involving insulin activation of insulin receptor isoforms and adenosine receptors and metabolism in the human placenta from GDM pregnancies.

Akt/mTOR Role in Human Foetoplacental Vascular Insulin Resistance in Diseases of Pregnancy.

Insulin resistance is characteristic of pregnancies where the mother shows metabolic alterations, such as preeclampsia (PE) and gestational diabetes mellitus (GDM), or abnormal maternal conditions such as pregestational maternal obesity (PGMO). Insulin signalling includes activation of insulin receptor substrates 1 and 2 (IRS1/2) as well as Src homology 2 domain-containing transforming protein 1, leading to activation of 44 and 42 kDa mitogen-activated protein kinases and protein kinase B/Akt (Akt) signalling cascades in the human foetoplacental vasculature. PE, GDM, and PGMO are abnormal conditions coursing with reduced insulin signalling, but the possibility of the involvement of similar cell signalling mechanisms is not addressed. This review aimed to determine whether reduced insulin signalling in PE, GDM, and PGMO shares a common mechanism in the human foetoplacental vasculature. Insulin resistance in these pathological conditions results from reduced Akt activation mainly due to inhibition of IRS1/2, likely due to the increased activity of the mammalian target of rapamycin (mTOR) resulting from lower activity of adenosine monophosphate kinase. Thus, a defective signalling via Akt/mTOR in response to insulin is a central and common mechanism of insulin resistance in these diseases of pregnancy. In this review, we summarise the cell signalling mechanisms behind the insulin resistance state in PE, GDM, and PGMO focused in the Akt/mTOR signalling pathway in the human foetoplacental endothelium.

Molecular implications of adenosine in obesity

Adenosine has broad activities in organisms due to the existence of multiple receptors, the differential adenosine concentrations necessary to activate these receptors and the presence of proteins able to synthetize, degrade or transport this nucleoside. All adenosine receptors have been reported to be involved in glucose homeostasis, inflammation, adipogenesis, insulin resistance, and thermogenesis, indicating that adenosine could participate in the process of obesity. Since adenosine seems to be associated with several effects, it is plausible that adenosine participates in the initiation and development of obesity or may function to prevent it. Thus, the purpose of this review was to explore the involvement of adenosine in adipogenesis, insulin resistance and thermogenesis, with the aim of understanding how adenosine could be used to avoid, treat or improve the metabolic state of obesity. Treatment with specific agonists and/or antagonists of adenosine receptors could reverse the obesity state, since adenosine receptors normalizes several mechanisms involved in obesity, such as lipolysis, insulin sensitivity and thermogenesis. Furthermore, obesity is a preventable state, and the specific activation of adenosine receptors could aid in the prevention of obesity. Nevertheless, for the treatment of obesity and its consequences, more studies and therapeutic strategies in addition to adenosine are necessary.

Effect of Hypoxia on the Calcium and Magnesium Content, Lipid Peroxidation Level, and Ca2+-ATPase Activity of Syncytiotrophoblast Plasma Membranes from Placental Explants

In the current study the possible relationship between the Ca2+/Mg2+ ratio of human syncytiotrophoblast plasma membranes and their lipid peroxidation and Ca2+-ATPase activity was determined. Syncytiotrophoblast plasma membranes of placental explants cultured under hypoxia increased their lipid peroxidation and Ca2+ content, diminished their Ca2+-ATPase activity, and kept their Mg2+ content unchanged. Membranes preincubated with different concentrations of Ca2+ increased their Ca2+ content without changes in their Mg2+ content. There is a direct relationship between Ca2+ content and lipid peroxidation of the membranes, as well as an inverse relationship between their Ca2+ content and Ca2+-ATPase activity. On the contrary, preincubation of membranes with different concentrations of Mg2+ showed a higher Mg2+ content without changing their lipid peroxidation and Ca2+-ATPase activity. Explants cultured under hypoxia in the presence of 4 mM MgSO4 showed similar values of lipid peroxidation and Ca2+-ATPase activity of their membranes compared to those of explants cultured under normoxia. Increased Ca2+ content of the membranes by interacting with negatively charged phospholipids could result in destabilizing effects of the membrane structure, exposing hydrocarbon chains of fatty acids to the action of free radicals. Mg2+ might exert a stabilizing effect of the membranes, avoiding their exposure to free radicals.

Foetoplacental communication via extracellular vesicles in normal pregnancy and preeclampsia

Intercellular communication is a critical process in biological mechanisms. During pregnancy foetoplacental tissues release a heterogeneous group of extracellular vesicles (EVs) that include exosomes, microvesicles, apoptotic bodies, and syncytial nuclear aggregates. These vesicles contain a complex cargo (proteins, DNA, mRNA transcripts, microRNAs, noncoding RNA, lipids, and other molecules) that actively participate in the maternal-foetal communication by modulating different processes during gestation for a successful foetal development. Each stage of human gestation is marked by events such as immunomodulation, proliferation, invasion, migration, and differentiation, among others, requiring EVs-mediated signalling to be nearby or distant target cells. Furthermore, EVs also associate with pregnancy pathologies such as preeclampsia and intrauterine growth restriction. This review addresses the role of EVs in human foetomaternal communication in normal pregnancy and preeclampsia.

Nitric oxide and pH modulation in gynaecological cancer

Nitric oxide plays several roles in cellular physiology, including control of the vascular tone and defence against pathogen infection. Neuronal, inducible and endothelial nitric oxide synthase (NOS) isoforms synthesize nitric oxide. Cells generate acid and base equivalents, whose physiological intracellular concentrations are kept due to membrane transport systems, including Na+/H+ exchangers and Na+/HCO3− transporters, thus maintaining a physiological pH at the intracellular (~7.0) and extracellular (~7.4) medium. In several pathologies, including cancer, cells are exposed to an extracellular acidic microenvironment, and the role for these membrane transport mechanisms in this phenomenon is likely. As altered NOS expression and activity is seen in cancer cells and because this gas promotes a glycolytic phenotype leading to extracellular acidosis in gynaecological cancer cells, a pro‐inflammatory microenvironment increasing inducible NOS expression in this cell type is feasible. However, whether abnormal control of intracellular and extracellular pH by cancer cells regards with their ability to synthesize or respond to nitric oxide is unknown. We, here, discuss a potential link between pH alterations, pH controlling membrane transport systems and NOS function. We propose a potential association between inducible NOS induction and Na+/H+ exchanger expression and activity in human ovary cancer. A potentiation between nitric oxide generation and the maintenance of a low extracellular pH (i.e. acidic) is proposed to establish a sequence of events in ovarian cancer cells, thus preserving a pro‐proliferative acidic tumour extracellular microenvironment. We suggest that pharmacological therapeutic targeting of Na+/H+ exchangers and inducible NOS may have benefits in human epithelial ovarian cancer.

Mechanisms of the effect of magnesium salts in preeclampsia

Preeclampsia is a heterogeneous pregnancy-specific syndrome associated with abnormal trophoblast invasion and endothelial dysfunction. Magnesium (Mg2+) level may be normal or decreased in women with preeclampsia. However, the use of Mg2+ salts, such as Mg2+ sulphate, are useful in reducing the pathophysiological consequences of preeclampsia with severe features and eclampsia. Although the mechanism of action of this Mg2+ salt is not well understood, the available evidence suggests a beneficial effect of Mg2+ for the mother and foetus. The mechanisms include a lower level of soluble fms-like tyrosine kinase 1 and endoglin, blockage of brain N-methyl-D-aspartate receptors, decreased inflammation mediators, activation of nitric oxide synthases, blockage of arginases, and reduced free radicals level. The maintenance of Mg2+ homeostasis in pregnancy is crucial for an appropriate pregnancy progression. Oral Mg2+ salts can be used for this purpose which could result in mitigating the deleterious consequences of this syndrome to the mother, foetus, and newborn.