Regulation Of Endothelial Barrier Function

The vascular endothelium lining the inner surface of blood vessels serves as the first interface for circulating blood components to interact with cells of the vascular wall and surrounding extravascular tissues. In addition to regulating blood delivery and perfusion, a major function of vascular endothelia, especially those in exchange microvessels (capillaries and postcapillary venules), is to provide a semipermeable barrier that controls blood–tissue exchange of fluids, nutrients, and metabolic wastes while preventing pathogens or harmful materials in the circulation from entering into tissues. During host defense against infection or tissue injury, endothelial barrier dysfunction occurs as a consequence as well as cause of inflammatory responses. Plasma leakage disturbs fluid homeostasis and impairs tissue oxygenation, a pathophysiological process contributing to multiple organ dysfunction associated with trauma, infection, metabolic disorder, and other forms of disease. In this book, we provide an updated overview of microvascular endothelial barrier structure and function in health and disease. The discussion is initiated with the basic physiological principles of fluid and solute transport across microvascular endothelium, followed by detailed information on endothelial cell–cell and cell–matrix interactions and the experimental techniques that are employed to measure endothelial permeability. Further discussion focuses on the signaling and molecular mechanisms of endothelial barrier responses to various stimulations or drugs, as well as their relevance to several common clinical conditions. Taken together, this book provides a comprehensive analysis of microvascular endothelial cell and molecular pathophysiology. Such information will assist scientists and clinicians in advanced basic and clinical research for improved health care.

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

The microcirculation is highly responsive to, and a vital participant in, the inflammatory response. All segments of the microvasculature (arterioles, capillaries, and venules) exhibit characteristic phenotypic changes during inflammation that appear to be directed toward enhancing the delivery of inflammatory cells to the injured/infected tissue, isolating the region from healthy tissue and the systemic circulation, and setting the stage for tissue repair and regeneration. The best characterized responses of the microcirculation to inflammation include impaired vasomotor function, reduced capillary perfusion, adhesion of leukocytes and platelets, activation of the coagulation cascade, and enhanced thrombosis, increased vascular permeability, and an increase in the rate of proliferation of blood and lymphatic vessels. A variety of cells that normally circulate in blood (leukocytes, platelets) or reside within the vessel wall (endothelial cells, pericytes) or in the perivascular space (mast cells, macrophages) are activated in response to inflammation. The activation products and chemical mediators released from these cells act through different well-characterized signaling pathways to induce the phenotypic changes in microvessel function that accompany inflammation. Drugs that target a specific microvascular response to inflammation, such as leukocyte-endothelial cell adhesion or angiogenesis, have shown promise in both the preclinical and clinical studies of inflammatory disease. Future research efforts in this area will likely identify new avenues for therapeutic intervention in inflammation. Table of Contents: Introduction / Historical Perspectives / Anatomical Considerations / Impaired Vasomotor Responses / Capillary Perfusion / Angiogenesis / Leukocyte-Endothelial Cell Adhesion / Platelet-Vessel Wall Interactions / Coagulation and Thrombosis / Endothelial Barrier Dysfunction / Epilogue / References

This book presents a concise synthesis of the current knowledge and recent advances in the structure, organization and functional role of the cytoskeleton in endothelial cells. Particular attention has been given to the different features of the regulation of vascular function mediated by the endothelium. Since cytoskeleton is a scaffolding element that regulates the architecture of the cell and additionally controls several fundamental aspects of intracellular signaling, this book will serve as a comprehensive resource for those interested in these fascinating biological processes associated with vascular biology. The book has been divided into two major sections: general aspects of the endothelial cytoskeleton and the role of the role of the endothelial cytoskeleton in different functions of the vascular wall.

The partition of fluid between the vascular and interstitial compartments is regulated by forces (hydrostatic and oncotic) operating across the microvascular walls and the surface areas of permeable structures comprising the endothelial barrier to fluid and solute exchange, as well as within the extracellular matrix and lymphatics. In addition to its role in the regulation of vascular volume, transcapillary fluid filtration also allows for continuous turnover of water bathing tissue cells, providing the medium for diffusional flux of oxygen and nutrients required for cellular metabolism and removal of metabolic byproducts. Transendothelial volume flow has also been shown to influence vascular smooth muscle tone in arterioles, hydraulic conductivity in capillaries, and neutrophil transmigration across postcapillary venules, while the flow of this filtrate through the interstitial spaces functions to modify the activities of parenchymal, resident tissue, and metastasizing tumor cells. Likewise, the flow of lymph, which is driven by capillary filtration, is important for the transport of immune and tumor cells, antigen delivery to lymph nodes, and for return of filtered fluid and extravasated proteins to the blood. Given this background, the aims of this treatise are to summarize our current understanding of the factors involved in the regulation of transcapillary fluid movement, how fluid movements across the endothelial barrier and through the interstitium and lymphatic vessels influence cell function and behavior, and the pathophysiology of edema formation. Table of Contents: Fluid Movement Across the Endothelial Barrier / The Interstitium / The Lymphatic Vasculature / Pathophysiology of Edema Formation

This wide ranging work provides a complete representation of the present state of knowledge of the vascular endothelium. The volume comprises 20 chapters by experts who have made significant contributions to research in the vascular endothelium. The text discusses the structure, development and function of the normal vascular endothelium, considers conditions that lead to the disruption of vascular physiology and provides a comprehensive description of pathologies and their treatment.