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Preeclampsia (PE) is characterized by endothelial cell (EC) dysfunction, loss of vasodilatory capacity, and loss of EC integrity. In a healthy pregnancy, there is a 'normal' increase in inflammatory factors, including TNF-[alpha]. TNF-[alpha] abundance increases beyond compensatory limits in PE. The first aim examined the requirement of SRC (using inhibitors PP2, PP3, SRC-I1, Dasatinib*, Saracatinib*, *denotes clinical inhibitor), MEK (using inhibitors U0126, PD98059, PD0325901), and P38MAPK (using inhibitors SB203580, BIRB0796) in maintaining resistance (a hallmark of EC integrity) in P-UAECs via ECIS in the absence and presence of TNF-[alpha]. Our results showed that these inhibitors (and combinations) have differential responses in the absence and presence of TNF-[alpha]. While some inhibitors (and combinations) were stimulatory in the absence, none were able to provide complete or full protection in the presence of TNF-[alpha]-mediated destruction. We concluded the resistance of the P-UAEC monolayer is regulated by SRC, MEK, and P38MAPK. The second aim was to identify the effect of other inflammatory mediators, including interleukin 1[beta] (IL-1[beta]), interleukin 6 (IL-6), and interleukin 8 (IL-8) in the absence and presence of TNF-[alpha] (using P-UAECs via ECIS). In addition, we attempted to discern the effects of GP130 and the downstream signaling pathway JAK (using inhibitor AG490) and SRC (using inhibitor PP2) on EC integrity in the absence and presence of TNF-[alpha], IL-1[beta], or TNF+IL-1[beta]. In the absence of TNF-[alpha] several inhibitors (or combinations) increased resistances above control. However, none of the agents tested (alone or in combination) could prevent or provide full rescue of P-UAEC integrity from the effects of TNF-[alpha] alone or the IL-1[beta]+TNF-[alpha] combination. We conclude that while IL-1[beta] and TNF-[alpha] share some signaling pathways, they are clearly under distinct mechanisms of control. In the third and final aim, we examined if P-UAECs undergo cell surface changes (a process known as immune modulation) in response to long-term exposure (20hrs) to different cytokines TNF-[alpha] , IL-1[beta], or IFN-[gamma] and identify if there were subpopulations of cells (using multiparameter flow cytometry experiments). The novel discovery of this collection of work is that PUAEC subpopulations were formed and changes of these populations depend upon the type of cytokine treatment. Immune modulation is indeed at play in regulating endothelial subpopulations, damage, and, therefore, the pathogenesis 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.
The endothelium, a monolayer of endothelial cells, constitutes the inner cellular lining of the blood vessels (arteries, veins and capillaries) and the lymphatic system, and therefore is in direct contact with the blood/lymph and the circulating cells. The endothelium is a major player in the control of blood fluidity, platelet aggregation and vascular tone, a major actor in the regulation of immunology, inflammation and angiogenesis, and an important metabolizing and an endocrine organ. Endothelial cells controls vascular tone, and thereby blood flow, by synthesizing and releasing relaxing and contracting factors such as nitric oxide, metabolites of arachidonic acid via the cyclooxygenases, lipoxygenases and cytochrome P450 pathways, various peptides (endothelin, urotensin, CNP, adrenomedullin, etc.), adenosine, purines, reactive oxygen species and so on. Additionally, endothelial ectoenzymes are required steps in the generation of vasoactive hormones such as angiotensin II. An endothelial dysfunction linked to an imbalance in the synthesis and/or the release of these various endothelial factors may explain the initiation of cardiovascular pathologies (from hypertension to atherosclerosis) or their development and perpetuation. Table of Contents: Introduction / Multiple Functions of the Endothelial Cells / Calcium Signaling in Vascular Cells and Cell-to-Cell Communications / Endothelium-Dependent Regulation of Vascular Tone / Conclusion / References
Chesley’s Hypertensive Disorders in Pregnancy continues its tradition as one of the beacons to guide the field of preeclampsia research, recognized for its uniqueness and utility. Hypertensive disorders remain one the major causes of maternal and fetal morbidity and death. It is also a leading cause of preterm birth now known to be a risk factor in remote cardiovascular disease. Despite this the hypertensive disorders remain marginally studied and management is often controversial. The fourth edition of Chesley’s Hypertensive Disorders in Pregnancy focuses on prediction, prevention, and management for clinicians, and is an essential reference text for clinical and basic investigators alike. Differing from other texts devoted to preeclampsia, it covers the whole gamut of high blood pressure, and not just preeclampsia. Features new chapters focusing on recent discoveries in areas such as fetal programming, genomics/proteomics, and angiogenesis Includes extensive updates to chapters on epidemiology, etiological considerations, pathophysiology, prediction, prevention, and management Discusses the emerging roles of metabolic syndrome and obesity and the increasing incidence of preeclampsia Each section overseen by one of the editors; each chapter co-authored by one of the editors, ensuring coherence throughout book
The endothelium enables communication between blood and tissues and is actively involved in cardiovascular homeostasis. Endothelial dysfunction has been recognized as an early step in the development of cardiovascular diseases: respectively, endothelium represents a potential therapeutic niche with multiple targets. The purpose of the book is to point out some recent findings of endothelial physiology and pathophysiology emphasizing various aspects of endothelial dysfunction connected to the body's internal and external environment. While basic features of the endothelium are presented in an introductory chapter, the authors of the following 17 chapters have provided extensive insight into some selected topics of endothelial (dys)function. The book would hopefully be useful for anyone interested in recapitulating endothelial (patho)physiology and expanding knowledge of molecular mechanisms involved in endothelial dysfunction, relevant also for further clinical investigations.
Endothelium and Cardiovascular Diseases: Vascular Biology and Clinical Syndromes provides an in-depth examination of the role of endothelium and endothelial dysfunction in normal vascular function, and in a broad spectrum of clinical syndromes, from atherosclerosis, to cognitive disturbances and eclampsia. The endothelium is a major participant in the pathophysiology of diseases, such as atherosclerosis, diabetes and hypertension, and these entities are responsible for the largest part of cardiovascular mortality and morbidly. Over the last decade major new discoveries and concepts involving the endothelium have come to light. This important reference collects this data in an easy to reference resource. Written by known experts, and covering all aspects of endothelial function in health and disease, this reference represents an assembly of recent knowledge that is essential to both basic investigators and clinicians. Provides a complete overview of endothelial function in health and diseases, along with an assessment of new information Includes coverage of groundbreaking areas, including the artificial LDL particle, the development of a new anti-erectile dysfunction agent, a vaccine for atherosclerosis, coronary calcification associated with red wine, and the interplay of endoplasmic reticulum/oxidative stress Explores the genetic features of endothelium and the interaction between basic knowledge and clinical syndromes
Vascular Responses to Pathogens focuses on the growing research from leaders in the field for both the short and long-term impact of pathogens on the vasculature. It discusses various organisms, including bacteria, parasites, and viruses, and their role in key events leading to vascular disease. Formatted to discuss the topic of the interaction of pathogens with the vascular rather than individual diseases described separately, this reference demonstrates that common mechanisms are at play in many different diseases because they have a similar context, their vasculature. This all-inclusive reference book is a must-have tool for researchers and practicing clinicians in the areas of vascular biology, microvasculature, cardiology, and infectious disease. Covers a wide spectrum of organisms and provides analysis of pathogens and current therapeutic strategies in the context of their vasculature Provides detailed perspectives on key components contributing to vascular pathogens from leaders in the field Interfaces between both vascular biology and microbiology by encompassing information on how pathogens affect both macro and microvasculature Includes coverage of the clinical aspects of sepsis and current therapeutic strategies and anti-sepsis drugs
Mast cells are tissue-localized cells that play an important role in immunity and inflammation. Following an offensive event they act as cellular sensors that via the activation of cell surface receptors launch a cellular response culminating in the release of a whole set of inflammatory mediators and products. This response is initially destined to restore tissue homeostasis, but in case of chronic injury or deregulation also promotes pathology. To further understand the action of mast cells in their environmental context it is necessary to decipher the molecular mechanisms of their activation as well as the ensuing cellular responses. This will allow identification of new strategies to promote their beneficial actions or, at the contrary, to interfere with their pathological consequences. While in the past many studies have focused on responses engaged by high affinity IgE receptor because of its implication in the allergic response, it has become clear that mast cells can be activated by multiple types of receptors initiating an intense molecular crosstalk between receptors and signaling pathways that can either synergize, antagonize and in some cases produce new types of responses. Mast cells can indeed react with an astounding diverse array of cellular responses that sometimes are engaged selectively. This Research Topic will focus on selected articles that shed some new light on the molecular mechanisms of mast cell activation, the possible crosstalk between signaling pathways and the ensuing cellular responses that allow mast cells to act as cellular sensors in tissues.