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Journal of Internal Medicine Jul 2016Cells are covered by a surface layer of glycans that is referred to as the 'glycocalyx'. In this review, we focus on the role of the glycocalyx in vascular diseases... (Review)
Review
Cells are covered by a surface layer of glycans that is referred to as the 'glycocalyx'. In this review, we focus on the role of the glycocalyx in vascular diseases (atherosclerosis, stroke, hypertension, kidney disease and sepsis) and cancer. The glycocalyx and its principal glycosaminoglycans [heparan sulphate (HS) and hyaluronic acid (HA)] and core proteins (syndecans and glypicans) are degraded in vascular diseases, leading to a breakdown of the vascular permeability barrier, enhanced access of leucocytes to the arterial intima that propagate inflammation and alteration of endothelial mechanotransduction mechanisms that protect against disease. By contrast, the glycocalyx on cancer cells is generally robust, promoting integrin clustering and growth factor signalling, and mechanotransduction of interstitial flow shear stress that is elevated in tumours to upregulate matrix metalloproteinase release which enhances cell motility and metastasis. HS and HA are consistently elevated on cancer cells and are associated with tumour growth and metastasis. Later, we will review the agents that might be used to enhance or protect the glycocalyx to combat vascular disease, as well as a different set of compounds that can degrade the cancer cell glycocalyx to suppress cell growth and metastasis. It is clear that what is beneficial for either vascular disease or cancer will not be so for the other. The overarching conclusions are that (i) the importance of the glycocalyx in human medicine is only beginning to be recognized, and (ii) more detailed studies of glycocalyx involvement in vascular diseases and cancer will lead to novel treatment modalities.
Topics: Animals; Capillary Permeability; Glycocalyx; Glycoproteins; Humans; Neoplasms; Proteoglycans; Vascular Diseases
PubMed: 26749537
DOI: 10.1111/joim.12465 -
Shock (Augusta, Ga.) Mar 2016Sepsis affects practically all aspects of endothelial cell (EC) function and is thought to be the key factor in the progression from sepsis to organ failure. Endothelial... (Review)
Review
Sepsis affects practically all aspects of endothelial cell (EC) function and is thought to be the key factor in the progression from sepsis to organ failure. Endothelial functions affected by sepsis include vasoregulation, barrier function, inflammation, and hemostasis. These are among other mechanisms often mediated by glycocalyx shedding, such as abnormal nitric oxide metabolism, up-regulation of reactive oxygen species generation due to down-regulation of endothelial-associated antioxidant defenses, transcellular communication, proteases, exposure of adhesion molecules, and activation of tissue factor. This review covers current insight in EC-associated hemostatic responses to sepsis and the EC response to inflammation. The endothelial cell lining is highly heterogeneous between different organ systems and consequently also in its response to sepsis. In this context, we discuss the response of the endothelial cell lining to sepsis in the kidney, liver, and lung. Finally, we discuss evidence as to whether the EC response to sepsis is adaptive or maladaptive. This study is a result of an Acute Dialysis Quality Initiative XIV Sepsis Workgroup meeting held in Bogota, Columbia, between October 12 and 15, 2014.
Topics: Animals; Down-Regulation; Endothelial Cells; Endothelium; Glycocalyx; Hemostasis; Humans; Nitric Oxide; Organ Specificity; Sepsis; Thromboplastin; Up-Regulation
PubMed: 26871664
DOI: 10.1097/SHK.0000000000000473 -
Pflugers Archiv : European Journal of... Jun 2007This review aims at presenting state-of-the-art knowledge on the composition and functions of the endothelial glycocalyx. The endothelial glycocalyx is a network of... (Review)
Review
This review aims at presenting state-of-the-art knowledge on the composition and functions of the endothelial glycocalyx. The endothelial glycocalyx is a network of membrane-bound proteoglycans and glycoproteins, covering the endothelium luminally. Both endothelium- and plasma-derived soluble molecules integrate into this mesh. Over the past decade, insight has been gained into the role of the glycocalyx in vascular physiology and pathology, including mechanotransduction, hemostasis, signaling, and blood cell-vessel wall interactions. The contribution of the glycocalyx to diabetes, ischemia/reperfusion, and atherosclerosis is also reviewed. Experimental data from the micro- and macrocirculation alludes at a vasculoprotective role for the glycocalyx. Assessing this possible role of the endothelial glycocalyx requires reliable visualization of this delicate layer, which is a great challenge. An overview is given of the various ways in which the endothelial glycocalyx has been visualized up to now, including first data from two-photon microscopic imaging.
Topics: Animals; Atherosclerosis; Diabetes Mellitus; Endothelium, Vascular; Glycocalyx; Glycoproteins; Humans; Mechanotransduction, Cellular; Microscopy; Models, Cardiovascular; Proteoglycans; Reperfusion Injury; Solubility
PubMed: 17256154
DOI: 10.1007/s00424-007-0212-8 -
Journal of Thrombosis and Haemostasis :... Feb 2019The vascular endothelial surface is coated by the glycocalyx, a ubiquitous gel-like layer composed of a membrane-binding domain that contains proteoglycans,... (Review)
Review
The vascular endothelial surface is coated by the glycocalyx, a ubiquitous gel-like layer composed of a membrane-binding domain that contains proteoglycans, glycosaminoglycan side-chains, and plasma proteins such as albumin and antithrombin. The endothelial glycocalyx plays a critical role in maintaining vascular homeostasis. However, this component is highly vulnerable to damage and is also difficult to examine. Recent advances in analytical techniques have enabled biochemical, visual and computational investigation of this vascular component. The glycocalyx modulates leukocyte-endothelial interactions, thrombus formation and other processes that lead to microcirculatory dysfunction and critical organ injury in sepsis. It also acts as a regulator of vascular permeability and contains mechanosensors as well as receptors for growth factors and anticoagulants. During the initial onset of sepsis, the glycocalyx is damaged and circulating levels of glycocalyx components, including syndecans, heparan sulfate and hyaluronic acid, can be measured and are reportedly useful as biomarkers for sepsis. Also, a new methodology using side-stream dark-field imaging is now clinically available for assessing the glycocalyx. Multiple factors including hypervolemia and hyperglycemia are toxic to the glycocalyx, and several agents have been proposed as therapeutic modalities, although no single treatment has been proven to be clinically effective. In this article, we review the derangement of the glycocalyx in sepsis. Despite the accumulated knowledge regarding the important roles of the glycocalyx, the relationship between derangement of the endothelial glycocalyx and severity of sepsis or disseminated intravascular coagulation has not been adequately elucidated and further work is needed.
Topics: Animals; Blood Coagulation; Capillary Permeability; Cell Adhesion; Endothelial Cells; Glycocalyx; Humans; Sepsis; Signal Transduction
PubMed: 30582882
DOI: 10.1111/jth.14371 -
Comprehensive Physiology Aug 2022The glycocalyx is a polysaccharide structure that protrudes from the body of a cell. It is primarily conformed of glycoproteins and proteoglycans, which provide...
The glycocalyx is a polysaccharide structure that protrudes from the body of a cell. It is primarily conformed of glycoproteins and proteoglycans, which provide communication, electrostatic charge, ionic buffering, permeability, and mechanosensation-mechanotransduction capabilities to cells. In blood vessels, the endothelial glycocalyx that projects into the vascular lumen separates the vascular wall from the circulating blood. Such a physical location allows a number of its components, including sialic acid, glypican-1, heparan sulfate, and hyaluronan, to participate in the mechanosensation-mechanotransduction of blood flow-dependent shear stress, which results in the synthesis of nitric oxide and flow-mediated vasodilation. The endothelial glycocalyx also participates in the regulation of vascular permeability and the modulation of inflammatory responses, including the processes of leukocyte rolling and extravasation. Its structural architecture and negative charge work to prevent macromolecules greater than approximately 70 kDa and cationic molecules from binding and flowing out of the vasculature. This also prevents the extravasation of pathogens such as bacteria and virus, as well as that of tumor cells. Due to its constant exposure to shear and circulating enzymes such as neuraminidase, heparanase, hyaluronidase, and matrix metalloproteinases, the endothelial glycocalyx is in a continuous process of degradation and renovation. A balance favoring degradation is associated with a variety of pathologies including atherosclerosis, hypertension, vascular aging, metastatic cancer, and diabetic vasculopathies. Consequently, ongoing research efforts are focused on deciphering the mechanisms that promote glycocalyx degradation or limit its syntheses, as well as on therapeutic approaches to improve glycocalyx integrity with the goal of reducing vascular disease. © 2022 American Physiological Society. Compr Physiol 12: 1-31, 2022.
Topics: Endothelium, Vascular; Glycocalyx; Heparitin Sulfate; Humans; Mechanotransduction, Cellular; Stress, Mechanical
PubMed: 35997082
DOI: 10.1002/cphy.c210029 -
The New England Journal of Medicine Sep 2013
Review
Topics: Albumins; Colloids; Crystalloid Solutions; Fluid Therapy; Glycocalyx; History, 19th Century; History, 20th Century; Humans; Isotonic Solutions; Rehydration Solutions; Resuscitation
PubMed: 24066745
DOI: 10.1056/NEJMra1208627 -
British Journal of Anaesthesia Mar 2012I.V. fluid therapy does not result in the extracellular volume distribution expected from Starling's original model of semi-permeable capillaries subject to hydrostatic... (Review)
Review
I.V. fluid therapy does not result in the extracellular volume distribution expected from Starling's original model of semi-permeable capillaries subject to hydrostatic and oncotic pressure gradients within the extracellular fluid. Fluid therapy to support the circulation relies on applying a physiological paradigm that better explains clinical and research observations. The revised Starling equation based on recent research considers the contributions of the endothelial glycocalyx layer (EGL), the endothelial basement membrane, and the extracellular matrix. The characteristics of capillaries in various tissues are reviewed and some clinical corollaries considered. The oncotic pressure difference across the EGL opposes, but does not reverse, the filtration rate (the 'no absorption' rule) and is an important feature of the revised paradigm and highlights the limitations of attempting to prevent or treat oedema by transfusing colloids. Filtered fluid returns to the circulation as lymph. The EGL excludes larger molecules and occupies a substantial volume of the intravascular space and therefore requires a new interpretation of dilution studies of blood volume and the speculation that protection or restoration of the EGL might be an important therapeutic goal. An explanation for the phenomenon of context sensitivity of fluid volume kinetics is offered, and the proposal that crystalloid resuscitation from low capillary pressures is rational. Any potential advantage of plasma or plasma substitutes over crystalloids for volume expansion only manifests itself at higher capillary pressures.
Topics: Basement Membrane; Blood Proteins; Capillary Permeability; Endothelium, Vascular; Extracellular Matrix; Fluid Therapy; Glycocalyx; Humans; Microcirculation; Models, Cardiovascular; Plasma Substitutes
PubMed: 22290457
DOI: 10.1093/bja/aer515 -
The American Journal of Pathology Apr 2020Along with the recognition of a crucial role played by endothelial dysfunction secondarily igniting cardiovascular, pulmonary, and renal complications, investigational... (Review)
Review
Along with the recognition of a crucial role played by endothelial dysfunction secondarily igniting cardiovascular, pulmonary, and renal complications, investigational focus has extended toward endothelial glycocalyx. This delicate coating of cells, including the vascular endothelium, regulates permeability, leukocyte traffic, nitric oxide production, and coagulation, and harbors diverse growth and survival factors. In this brief overview, we discuss the metabolic signatures of sepsis as they relate to the loss of glycocalyx integrity and highlight the contribution of several proteases, heparanase, and hyaluronidase to the shedding of glycocalyx. Clinical manifestations of glycocalyx degradation in unraveling acute respiratory distress syndrome and the cardiovascular, microcirculatory, and renal complications of sepsis are concisely presented. Finally, we list therapeutic strategies for preventing the degradation of, and for restoration of, the glycocalyx.
Topics: Animals; Endothelium, Vascular; Endotoxemia; Glycocalyx; Humans; Sepsis
PubMed: 32035882
DOI: 10.1016/j.ajpath.2019.06.017 -
International Journal of Molecular... Dec 2022Sepsis carries a substantial risk of morbidity and mortality in newborns, especially preterm-born neonates. Endothelial glycocalyx (eGC) is a carbohydrate-rich layer... (Review)
Review
Sepsis carries a substantial risk of morbidity and mortality in newborns, especially preterm-born neonates. Endothelial glycocalyx (eGC) is a carbohydrate-rich layer lining the vascular endothelium, with important vascular barrier function and cell adhesion properties, serving also as a mechano-sensor for blood flow. eGC shedding is recognized as a fundamental pathophysiological process generating microvascular dysfunction, which in turn contributes to multiple organ failure and death in sepsis. Although the disruption of eGC and its consequences have been investigated intensively in the adult population, its composition, development, and potential mechanisms of action are still poorly studied during the neonatal period, and more specifically, in neonatal sepsis. Further knowledge on this topic may provide a better understanding of the molecular mechanisms that guide the sepsis pathology during the neonatal period, and would increase the usefulness of endothelial glycocalyx dysfunction as a diagnostic and prognostic biomarker. We reviewed several components of the eGC that help to deeply understand the mechanisms involved in the eGC disruption during the neonatal period. In addition, we evaluated the potential of eGC components as biomarkers and future targets to develop therapeutic strategies for neonatal sepsis.
Topics: Infant, Newborn; Adult; Humans; Neonatal Sepsis; Glycocalyx; Endothelium, Vascular; Sepsis; Biomarkers
PubMed: 36613805
DOI: 10.3390/ijms24010364 -
American Journal of Physiology. Cell... Aug 2022The growing recognition of abundance of oscillating functions in biological systems has motivated this brief overview, which narrows down on the microvasculature.... (Review)
Review
The growing recognition of abundance of oscillating functions in biological systems has motivated this brief overview, which narrows down on the microvasculature. Specifically, it encompasses self-sustained oscillations of blood flow, hematocrit, and viscosity at bifurcations; blood flow effects on the oscillations of endothelial glycocalyx, mechanotransduction, and its termination to prime endothelial cells for the subsequent mechanical signaling event; oscillating affinity of hyaluronan-CD44 binding domain; spontaneous contractility of actomyosin complexes in the cortical actin web and its effects on the tension of the plasma membrane; reversible effects of sirtuin-1 on endothelial glycocalyx; and effects of plasma membrane tension on endo- and exocytosis. Some potential interactions between those oscillators, and their coupling, are discussed together with their transition into chaotic movements. Future in-depth understanding of the oscillatory activities in the microvasculature could serve as a guide to its chronotherapy under pathological conditions.
Topics: Actin Cytoskeleton; Endothelial Cells; Glycocalyx; Mechanotransduction, Cellular; Microvessels
PubMed: 35759436
DOI: 10.1152/ajpcell.00170.2022