Maternal monocytes in pregnancy and preeclampsia in humans and in rats

AbstractMonocytes are short-lived cells, arising from the bone marrow and maturing in the circulation. They play an important role in immune responses and are thought to be important for healthy pregnancy. In humans, 3 subpopulations of monocytes have been identified: classical, intermediate and non-classical monocytes. These subpopulations have different functions and phenotypical characteristics. Healthy pregnancy is characterized by a pro-inflammatory condition, with increased numbers of monocytes and monocyte activation as well as with increased numbers of intermediate monocytes and decreased numbers of classical monocytes. This may suggest monocyte maturation. Preeclampsia is an important pregnancy complication characterized by hypertension and proteinuria developing in the second half of pregnancy. The pathophysiology of preeclampsia is associated with further activation of the inflammatory response, further activation of monocytes and further monocyte maturation. In the present review we focus on the role of monocyte activation and maturation in healthy and preeclamptic pregnancy

Monocytes and macrophages in pregnancy and pre-eclampsia

Preeclampsia is an important complication in pregnancy, characterized byhypertension and proteinuria in the second half of pregnancy. Generalizedactivation of the inflammatory response is thought to play a role in thepathogenesis of preeclampsia. Monocytes may play a central role in thisinflammatory response. Monocytes are short lived cells, that mature in thecirculation and invade into tissues upon an inflammatory stimulus anddevelop into macrophages. Macrophages are abundantly present in theendometrium and play a role in implantation and placentation in normalpregnancy. In preeclampsia, these macrophages appear to be present in largernumbers and are also activated. In the present review we focused on the roleof monocytes and macrophages in the pathophysiology of preeclampsia

Molecular and Cellular Mechanisms of Preeclampsia

This Special Issue on the “Molecular and Cellular Mechanisms of Preeclampsia” belongs to the section “Molecular Pathology, Diagnostics, and Therapeutics” of the International Journal of Molecular Sciences. It was a very successful Special Issue as it contains 20 published papers, including one editorial, nine original research papers, and ten reviews on the topic. The original publications cover a wide spectrum of topics, including alterations and involvement of specific factors during preeclampsia, new non-invasive technologies to identify changes, new treatment options, animal models, gender aspects, and effects of the pregnancy pathology later in life. The review publications again cover a wide spectrum of topics, including factors and pathways involved in preeclampsia, effects on the maternal vascular and immune systems, effects on the placenta and the trophoblast, epigenetic changes, new preventive strategies, and new views on the current hypotheses on preeclampsia. Taken together, this Special Issue gives a fantastic overview on a broad spectrum of topics, all of which are important to identify the real etiology of preeclampsia and to finally develop real treatment options

Angiogenesis and chronic kidney disease

The number of patients requiring renal replacement therapy due to end-stage renal disease (ESRD) is increasing worldwide. The prevalence of chronic kidney disease (CKD), and the importance of CKD as a risk factor in development of ESRD and in complicating cardiovascular disease (CVD) have been confirmed. In recent years, the involvement of angiogenesis-related factors in the progression of CKD has been studied, and the potential therapeutic effects on CKD of modulating these factors have been identified. Vascular endothelial growth factor (VEGF)-A, a potent pro-angiogenic factor, is involved in the development of the kidney, in maintenance of the glomerular capillary structure and filtration barrier, and in the renal repair process after injury. VEGF-A is also involved in the development of early diabetic nephropathy, demonstrated by the therapeutic effects of anti-VEGF-A antibody. Angiopoietin (Ang)-1 induces the maturation of newly formed blood vessels, and the therapeutic effects of Ang-1 in diabetic nephropathy have been described. In experimental models of diabetic nephropathy, the therapeutic effects of angiogenesis inhibitors, including angiostatin, endostatin and tumstatin peptides, the isocoumarin NM-3, and vasohibin-1, have been reported

The role of H2S bioavailability in endothelial dysfunction

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Endothelial dysfunction (EDF) reflects pathophysiological changes in the phenotype and functions of endothelial cells that result from and/or contribute to a plethora of cardiovascular diseases. We review the role of hydrogen sulfide (H2S) in the pathogenesis of EDF, one of the fastest advancing research topics. Conventionally treated as an environment pollutant, H2S is also produced in endothelial cells and participates in the fine regulation of endothelial integrity and functions. Disturbed H2S bioavailability has been suggested to be a novel indicator of EDF progress and prognosis. EDF manifests in different forms in multiple pathologies, but therapeutics aimed at remedying altered H2S bioavailability may benefit all.This work has been supported by a Discovery Grant from Natural Sciences and Engineering Research council of Canada to RW. CS has been supported by the American Diabetes Association, the National Institutes of Health of USA and the Shriners Hospitals for Children. FI has been supported by the National Institutes of Health of USA. MW has been supported by the Medical Research Council of UK. AA has been supported by programme grants from British Heart Foundation (RG/09/001/25940), Medical Research Council (G0700288), Royal Society and European Union. AP has been supported through an Aristeia grant (1436) that is co-financed by the European Union (ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning”. MW and AP are supported by the COST Action BM1005 (ENOG: European network on gasotransmitters)

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

The role and regulation of nitric oxide and oxidative stress in cardiometabolic disease : focus on preeclampsia

Cardiovascular (CVD) and metabolic diseases account for significant morbidity and mortality. Over the last decades, despite significant research and clinical effort, their global prevalence is estimated to further increase. This trend is similarly observed in the pregnant population, which increases the risk of cardiometabolic complications of pregnancy, such as preeclampsia (PE), which in turn, predisposes both the mother and offspring to increased future cardiovascular and metabolic risk. Disruption of the delicate balance between nitric oxide (NO) and reactive oxygen species (ROS) leads to a vicious pathogenic cycle which results in oxidative stress and systemic vascular dysfunction, key features of numerous CVD and metabolic diseases. In the vasculature, NO is predominantly synthesised via endothelial nitric oxide synthase (eNOS), although the nitrate-nitrite-NO pathway can serve as an additional source. The latter can be stimulated by dietary inorganic nitrate, found in leafy green vegetables and beetroot. The present thesis aimed to further explore the role of NO deficiency and oxidative stress in the pathogenesis of cardiometabolic disease, with focus on PE. We sought to dissect the mechanisms underlying the beneficial metabolic effects of dietary nitrate, investigate the role and mechanisms underlying erythrocrine function on endothelial homeostasis, assess the feasibility of conducting a clinical dietary nitrate intervention RCT in PE women and finally, examine how monocyte-derived factors perpetuate endothelial oxidative stress in PE. In study I, models of diet-induced metabolic syndrome and liver steatosis demonstrated a novel therapeutic role of dietary nitrate, mediated via modulation of AMPK signalling and NADPH oxidase-derived oxidative stress. In studies II, III, and IV, ex vivo incubations of red blood cells (RBCs) and healthy murine aortas were utilised to specifically evaluate functional RBCendothelial interactions. In study II, a lack of RBC eNOS induced endothelial dysfunction (ED), in part mediated via vascular arginase, elevated endothelial oxidative stress, and reduced NO bioavailability. In studies III and IV, RBCs isolated from PE patients, but not healthy pregnant women, induced ED, mediated via elevated arginase activity, reduced NO bioavailability, and elevated oxidative stress, in a contact-dependent manner. Study IV demonstrated that short term (7-day) dietary nitrate supplementation was well accepted and not associated with any adverse events. No significant differences in blood pressure changes were observed. Beneficial nitrate-independent effects on RBC-endothelial communication were observed ex vivo. In Study V an in vitro approach demonstrated that peripheral blood mononuclear cells (PBMCs) isolated from PE women increase oxidative stress and reduce NO bioavailability in the endothelium, which was prevented by antioxidant treatment (Silibinin). The balance between NO bioavailability and oxidative stress governs endothelial homeostasis. Beneficially targeting this delicate balance can be achieved via dietary inorganic nitrate, which holds safe, therapeutic promise for cardiometabolic disease. The RBC is a central player in mediating this balance in the vascular microenvironment, dysregulated erythrocrine function results in ED. Further investigation regarding RBC-endothelial signalling may provide insight into previously discarded therapeutic approaches for cardiometabolic diseases

S100B brain expression and plasma concentrations in a preeclampsia rat model

Objective: To assess brain damage using the neuroinflammation marker S100B in a preeclampsia rat model.Methods: Non-pregnant and pregnant rats were infused with saline or low-dose-endotoxin on day 14 of pregnancy. S100B expression in the brain (immunohistochemistry) and S100B plasma concentrations (ELISA) were studied.Results: No differences in S100B expression in brain tissue were observed between the four groups. Pregnant endotoxin treated animals did not show increased levels of plasma S100B levels as compared with control pregnant rats, while significantly higher plasma S100B levels were found in non-pregnant endotoxin versus pregnant endotoxin infused rats.Conclusion: Pregnancy nor experimental preeclampsia, alter S100B in rat brain, or in plasma. Increased plasma S100B in non-pregnant endotoxin-treated rats may indicate brain injury in these rats, whereas pregnancy might be protective.</p