Review

Authors: J M Tarbell, L M Cancel

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

Review

Authors: Sietze Reitsma, Dick W Slaaf, Hans Vink...

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

Authors: Christopher A Foote, Rogerio N Soares, Francisco I Ramirez-Perez...

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

Review

Authors: Can Ince, Philip R Mayeux, Trung Nguyen...

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

Authors: Sophia M Shi, Ryan J Suh, D Judy Shon...

The blood-brain barrier (BBB) is highly specialized to protect the brain from harmful circulating factors in the blood and maintain brain homeostasis. The brain endothelial glycocalyx layer, a carbohydrate-rich meshwork composed primarily of proteoglycans, glycoproteins and glycolipids that coats the BBB lumen, is a key structural component of the BBB. This layer forms the first interface between the blood and brain vasculature, yet little is known about its composition and roles in supporting BBB function in homeostatic and diseased states. Here we find that the brain endothelial glycocalyx is highly dysregulated during ageing and neurodegenerative disease. We identify significant perturbation in an underexplored class of densely O-glycosylated proteins known as mucin-domain glycoproteins. We demonstrate that ageing- and disease-associated aberrations in brain endothelial mucin-domain glycoproteins lead to dysregulated BBB function and, in severe cases, brain haemorrhaging in mice. Finally, we demonstrate that we can improve BBB function and reduce neuroinflammation and cognitive deficits in aged mice by restoring core 1 mucin-type O-glycans to the brain endothelium using adeno-associated viruses. Cumulatively, our findings provide a detailed compositional and structural mapping of the ageing brain endothelial glycocalyx layer and reveal important consequences of ageing- and disease-associated glycocalyx dysregulation on BBB integrity and brain health.

Topics: Glycocalyx; Animals; Blood-Brain Barrier; Aging; Mice; Male; Humans; Female; Neurodegenerative Diseases; Brain; Mice, Inbred C57BL; Endothelial Cells; Glycoproteins; Neuroinflammatory Diseases; Glycosylation; Polysaccharides; Dependovirus; Mucins

PubMed: 40011765
DOI: 10.1038/s41586-025-08589-9

Review

Authors: John A Myburgh, Michael G Mythen

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

Authors: Sangwoo Park, Marshall J Colville, Justin H Paek...

Cancer cell glycocalyx is a major line of defence against immune surveillance. However, how specific physical properties of the glycocalyx are regulated on a molecular level, contribute to immune evasion and may be overcome through immunoengineering must be resolved. Here we report how cancer-associated mucins and their glycosylation contribute to the nanoscale material thickness of the glycocalyx and consequently modulate the functional interactions with cytotoxic immune cells. Natural-killer-cell-mediated cytotoxicity is inversely correlated with the glycocalyx thickness of the target cells. Changes in glycocalyx thickness of approximately 10 nm can alter the susceptibility to immune cell attack. Enhanced stimulation of natural killer and T cells through equipment with chimeric antigen receptors can improve the cytotoxicity against mucin-bearing target cells. Alternatively, cytotoxicity can be enhanced through engineering effector cells to display glycocalyx-editing enzymes, including mucinases and sialidases. Together, our results motivate the development of immunoengineering strategies that overcome the glycocalyx armour of cancer cells.

Topics: Humans; Glycocalyx; Mucins; Antineoplastic Agents; Neoplasms

PubMed: 38361041
DOI: 10.1038/s41563-024-01808-0

Review

Authors: T E Woodcock, T M Woodcock

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

Authors: Qingyang Li, Shuai Shao, Zhenlai Zhu...

Dysfunction of vascular endothelial cells (ECs) facilitates imbalanced immune responses and tissue hyperinflammation. However, the heterogeneous functions of skin ECs and their underlying mechanism in dermatoses remain to be determined. Here, focusing on the pathogenic role of skin ECs in psoriasis, we characterized the molecular and functional heterogeneity of skin ECs from healthy individuals and psoriasis patients at the single-cell level. We found that endothelial glycocalyx destruction, a major feature of EC dysfunction in psoriasis, was a driving force during the process of T cell extravasation. Interestingly, we identified a skin EC subset, IGFBP7hi ECs, in psoriasis. This subset actively responded to psoriatic-related cytokine signaling, secreted IGFBP7, damaged the endothelial glycocalyx, exposed the adhesion molecules underneath, and prepared the endothelium for immune-cell adhesion and transmigration, thus aggravating skin inflammation. More importantly, we provided evidence in a psoriasis-like mouse model that anti-IGFBP7 treatment showed promising therapeutic effects for restoring the endothelial glycocalyx and alleviating skin inflammation. Taken together, our results depict the distinct functions of EC clusters in healthy and psoriatic skin, identify IGFBP7hi ECs as an active subset modulating vascular function and cutaneous inflammation, and indicate that targeting IGFBP7 is a potential therapeutic strategy in psoriasis.

Topics: Mice; Animals; Glycocalyx; Endothelial Cells; Psoriasis; T-Lymphocytes; Inflammation

PubMed: 36917196
DOI: 10.1172/JCI160451

Review

Authors: Michael S Goligorsky, Dong Sun

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