Adhesion of polymorphonuclear neutrophils (PMN) to coronary endothelium is a key event for cardiac ischemia/reperfusion injury. Adhesion molecules are normally harbored within the glycocalyx, clothing every healthy vascular endothelium, but shed by ischemia/reperfusion. Our aim was to show whether protection of the glycocalyx with either hydrocortisone or antithrombin can reduce postischemic leukocyte adhesion. Isolated guinea pig hearts, perfused with Krebs-Henseleit buffer, were subjected to 20 min of warm (37 degrees C) no-flow ischemia and consecutive 10 min of reperfusion, either in the absence or presence of hydrocortisone (10 microg/mL) or antithrombin (1 U/mL). An intracoronary bolus of 3 x 10 PMN was applied at the end of reperfusion but without prior contact to the drugs. The sequestration of PMN was calculated from the difference between coronary input and output of cells. Expression of the integrin CD11b on PMN was measured before and after coronary passage. Ischemia/reperfusion induced severe degradation of the glycocalyx (coronary venous syndecan-1 release, 171 +/- 15 ng/g heart vs. basal, 19 +/- 2 ng/g; heparan sulfate, 5.27 +/- 0.28 microg/g vs. basal, 0.26 +/- 0.06 microg/g) and increased PMN adhesion (38.1% +/- 3.5% vs. basal, 11.7% +/- 3.1%). Hydrocortisone and antithrombin both not only reduced glycocalyx shedding (syndecan-1 release, 34 +/- 6 ng/g and 26 +/- 5 ng/g; heparan sulfate, 1.96 +/- 0.24 microg/g and 1.28 +/- 0.2 microg/g, respectively), but also PMN adhesion (17.3% +/- 2.2% and 25.4% +/- 3.3%, respectively) after ischemia/reperfusion. Electron microscopy revealed a mostly intact coronary glycocalyx after pretreatment with either drug. Activation of PMN upon coronary passage was not influenced. Preservation of the glycocalyx mitigates postischemic PMN adhesion. Preconditioning with either hydrocortisone or antithrombin should, thus, alleviate vascular leakage, tissue edema, and inflammation.

Vascular remodeling induced by hemodynamic stimuli contributes to the pathophysiology of cardiovascular diseases. The importance of vascular cells (endothelial cells and smooth muscle cells) glycocalyx in the mechanotransduction of flow-induced shear stress at the cellular and molecular levels has been demonstrated over the past decade. However, its potential mechanotransduction role in vascular remodeling has triggered little attention. In the present study, a home-made apparatus was used to expose the rat abdominal aorta to sterile, flow or no flow, normal-pressure or high-pressure conditions for 4 days. The histomophometric, cellular, and molecular analysis of vessels were performed. The results showed that after exposing the vessels in the flow and high-pressure condition, the apoptotic rate, the cell number, and the RNA level of contractile marker gene smooth muscle 22 of smooth muscle cells were significantly increased, whereas the expression of nitric oxide synthase, α-smooth muscle actin, smoothelin, and calponion showed no significant differences compared with the flow and normal-pressure groups. Moreover, the histomophometric analysis of vascular walls suggested a remodeling induced by flow and high-pressure loading consistent with the classic hypertensive aortic phenotype, which is characterized by a thicker and more rigid vascular wall as well as increased aortic diameter. However, those phenomena were totally abolished after compromising the integrity of glycocalyx by the treatment of vessels with hyaluronidase, which provided evidence of the important mechanotransduction role of the vascular cells glycocalyx in vascular remodeling induced by hemodynamic stimuli.

Flow-induced mechanotransduction in vascular endothelial cells has been studied over the years with a major focus on putative connections between disturbed flow and atherosclerosis. Recent studies have brought in a new perspective that the glycocalyx, a structure decorating the luminal surface of vascular endothelium, may play an important role in the mechanotransduction. This study reports that modifying the amount of the glycocalyx affects both short-term and long-term shear responses significantly. It is well established that after 24 h of laminar flow, endothelial cells align in the direction of flow and their proliferation is suppressed. We report here that by removing the glycocalyx by using the specific enzyme heparinase III, endothelial cells no longer align under flow after 24 h and they proliferate as if there were no flow present. In addition, confluent endothelial cells respond rapidly to flow by decreasing their migration speed by 40% and increasing the amount of vascular endothelial cadherin in the cell-cell junctions. These responses are not observed in the cells treated with heparinase III. Heparan sulfate proteoglycans (a major component of the glycocalyx) redistribute after 24 h of flow application from a uniform surface profile to a distinct peripheral pattern with most molecules detected above cell-cell junctions. We conclude that the presence of the glycocalyx is necessary for the endothelial cells to respond to fluid shear, and the glycocalyx itself is modulated by the flow. The redistribution of the glycocalyx also appears to serve as a cell-adaptive mechanism by reducing the shear gradients that the cell surface experiences.

The endothelial cell glycocalyx, a structure coating the luminal surface of the vascular endothelium, and its related mechanotransduction have been studied by many over the last decade. However, the role of vascular smooth muscle cells (SMCs) glycocalyx in cell mechanotransduction has triggered little attention. This study addressed the role of heparan sulfate proteoglycans (HSPGs), a major component of the glycocalyx, in the shear-induced proliferation, migration, and nitric oxide (NO) production of the rat aortic smooth muscle cells (RASMCs). A parallel plate flow chamber and a peristaltic pump were employed to expose RASMC monolayers to a physiological level of shear stress (12 dyn/cm(2)). Heparinase III (Hep.III) was applied to selectively degrade heparan sulfate on the SMC surface. Cell proliferation, migration, and NO production rates were determined and compared among the following four groups of cells: 1) untreated with no flow, 2) Hep.III treatment with no flow, 3) untreated with flow of 12 dyn/cm(2) exposure, and 4) Hep.III treatment with flow of 12 dyn/cm(2) exposure. It was observed that flow-induced shear stress significantly suppressed SMC proliferation and migration, whereas cells preferred to aligning along the direction of flow and NO production were enhanced substantially. However, those responses were not found in the cells with Hep.III treatment. Under flow condition, the heparinase III-treated cells remained randomly oriented and proliferated as if there were no flow presence. Disruption of HSPG also enhanced wound closure and inhibited shear-induced NO production significantly. This study suggests that HSPG may play a pivotal role in mechanotransduction of SMCs.

INTRODUCTION:Postischemic injury to the coronary vascular endothelium, in particular to the endothelial glycocalyx, may provoke fluid extravasation. Shedding of the glycocalyx is triggered by redox stress encountered during reperfusion and should be alleviated by the radical scavenger nitric oxide (NO). The objective of this study was to investigate the effect of exogenous administration of NO during reperfusion on both coronary endothelial glycocalyx and vascular integrity. METHODS:Isolated guinea pig hearts were subjected to 15 minutes of warm global ischemia followed by 20 minutes of reperfusion in the absence (Control group) and presence (NO group) of 4 microM NO. In further experiments, the endothelial glycocalyx was enzymatically degraded by means of heparinase followed by reperfusion without (HEP group) and with NO (HEP+NO group). RESULTS:Ischemia and reperfusion severely damaged the endothelial glycocalyx. Shedding of heparan sulfate and damage assessed by electron microscopy were less in the presence of NO. Compared with baseline, coronary fluid extravasation increased after ischemia in the Control, HEP, and HEP+NO groups but remained almost unchanged in the NO group. Tissue edema was significantly attenuated in this group. Coronary vascular resistance rose by 25% to 30% during reperfusion, but not when NO was applied, irrespective of the state of the glycocalyx. Acute postischemic myocardial release of lactate was comparable in the four groups, whereas release of adenine nucleotide catabolites was reduced 42% by NO. The coronary venous level of uric acid, a potent antioxidant and scavenger of peroxynitrite, paradoxically decreased during postischemic infusion of NO. CONCLUSION:The cardioprotective effect of NO in postischemic reperfusion includes prevention of coronary vascular leak and interstitial edema and a tendency to forestall both no-reflow and degradation of the endothelial glycocalyx.

The study was aimed at testing the hypothesis that a toxic product of the reaction between superoxide (O(2)(-)) and nitric oxide (NO) mediates, not only endothelial dysfunction, but also endothelium-glycocalyx disruption, and increased neutrophil (PMN) accumulation in the heart subjected to ischemia/reperfusion (IR) injury. Accordingly, we studied if scavengers of either O(2)(-) or NO, or a compound that was reported to attenuate cardiac production of peroxynitrite, would prevent endothelial injury and subsequent PNM adhesion in IR heart. Langendorff-perfused guinea-pig hearts were subjected to 30 min ischemia/35 min reperfusion, and infusion of PMN between 15 and 25 min of the reperfusion. Coronary flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were used as measures of endothelium-dependent and -independent vascular function, respectively. PMN adhesion and endothelium glycocalyx ultrastructure were assessed in histological preparations. IR impaired the ACh, but not SNP, response by approximately 60%, caused endothelium-glycocalyx disruption, and approximately nine-fold increase in PMN adhesion. These alterations were prevented by superoxide dismutase (150 U/ml), NO synthase inhibitor, L-NAME (10 microM), NO scavenger, oxyhemoglobin (25 microM), and NO donor, SNAP (1 microM), and were not affected by catalase (600 u/ml). The glycocalyx-protective effect of these interventions preceded their effect on PMN adhesion. The data imply that PMN adhesion in IR guinea-pig heart is a process secondary to functional and/or structural changes in coronary endothelium, and that a toxic product of the reaction between superoxide and NO mediates these endothelial changes.

The endothelial glycocalyx covers the lumen of blood vessels throughout the body and plays an important role in endothelial homeostasis. Advances in electron microscopy techniques have provided clues to better understand the structure and composition of identical vascular endothelial glycocalyx. The morphology and thickness of the endothelial glycocalyx differ from organ to organ. The content of the endothelial glycocalyx covering the vascular lumen differs even in the brain, heart, and lungs, which have the same continuous capillaries. Various types of inflammation are known to attenuate the endothelial glycocalyx; however, we found that the morphology of the glycocalyx damaged by acute inflammation differed from that damaged by chronic inflammation. Acute inflammation breaks the endothelial glycocalyx unevenly, whereas chronic inflammation leads to the overall shortening of the endothelial glycocalyx. The same drug has different effects on the endothelial glycocalyx, depending on the location of the target blood vessels. This difference in response may reflect not only the size and shape of the endothelial glycocalyx but also the different constituents. In the cardiac tissue, the expression of glypican-1, a core protein of the endothelial glycocalyx, was enhanced. By contrast, in the pulmonary tissue, the expression of heparan sulfate 6-O-sulfotransferase 1 and endothelial cell-specific molecule-1 significantly increased in the treatment group compared with that in the no-treatment group. In this review, we present the latest findings on the evolution of the vascular endothelial glycocalyx and consider the microstructural differences.

The integrity of the endothelial glycocalyx (eGCX), a mixture of carbohydrates attached to proteins expressed on the surface of blood vessel endothelial cells (EC), is critical for the maintenance of homeostasis of the cardiovascular system and all systems of the human body, the endothelium being the critical component of the stroma of all tissues. Consequently, dysfunction of eGCX results in a dysfunctional cardiovascular wall and severe downstream cardiovascular events, which contribute to the onset of cardio- and cerebrovascular diseases and neurodegenerative disorders, as well as other age-related diseases (ARDs). The key role of eGCX dysfunction in the onset of ARDs is examined here, with a focus on the most prevalent neurological diseases: ischemic stroke and Alzheimer's disease. Furthermore, the advantages and limitations of some treatment strategies for anti-eGCX dysfunction are described, ranging from experimental drug therapies, which need to be better tested and explored not only in animal models but also in humans, as well as reprogramming, the use of nutraceuticals, which are emerging as regenerative and new approaches. The promotion of these strategies is essential to keep eGCX and endothelium healthy, as is the development of intravital (e.g., intravascular) tools to estimate eGCX health status and treatment efficacy, which could lead to advanced solutions to address ARDs.

Albuminuria is commonly used as a marker of kidney disease progression, but some evidence suggests that albuminuria also contributes to disease progression by inducing renal injury in specific disease conditions. Studies have confirmed that in patients with cardiovascular risk factors, such as diabetes and hypertension, endothelial damage drives progression of kidney disease and cardiovascular disease. A key mechanism that contributes to this process is the loss of the glycocalyx--a polysaccharide gel that lines the luminal endothelial surface and that normally acts as a barrier against albumin filtration. Degradation of the glycocalyx in response to endothelial activation can lead to albuminuria and subsequent renal and vascular inflammation, thus providing a pathophysiological framework for the clinical association of albuminuria with renal and cardiovascular disease progression. In this Review, we examine the likely mechanisms by which glycocalyx dysfunction contributes to kidney injury and explains the link between cardiovascular disease and albuminuria. Evidence suggests that glycocalyx dysfunction is reversible, suggesting that these mechanisms could be considered as therapeutic targets to prevent the progression of renal and cardiovascular disease. This possibility enables the use of existing drugs in new ways, provides an opportunity to develop novel therapies, and indicates that albuminuria should be reconsidered as an end point in clinical trials.

Dysfunctional endothelial cells are an essential contributor to the progression of diverse chronic cardiovascular, renal, and metabolic diseases. It manifests in impairment of nitric oxide-dependent vasorelaxation, vascular permeability, and leukocytes deterrent. While endothelial glycocalyx is known to regulate these functions, glycocalyx has been shown to be impaired in pathologic settings leading to endothelial dysfunction. Are these findings coincidental or are they indicative of a potential cooperation of the glycocalyx and the endothelium in inducing a dysfunctional phenotype? The main thrust of this overview is to advance a hypothesis on the existence of vicious circle relations between impaired endothelial glycocalyx and endothelial cell dysfunction. We briefly introduce physiology and pathology of blood flow-induced components of mechanotransduction in endothelial cells, as this function is dependent on glycocalyx and is critically involved in the development of endothelial dysfunction. Next, we present a series of experimental findings and arguments favoring the view on the impairment of mechanotransduction in dysfunctional endothelia. We advance the concept of feedback reinforcement between perturbed endothelial glycocalyx and progression of endothelial dysfunction and sketch therapeutic approaches to restore them. Among those we introduce our recently designed liposomal nanocarriers of preassembled glycocalyx and present evidence of their ability to expeditiously restore endothelial mechanotransduction.

Malaria is estimated to kill 438 000 people annually, mostly due to severe malaria, which is closely associated with microcirculatory vasculopathy, although its pathogenesis remains incompletely understood. Here, we propose that the largely ignored glycocalyx of the vascular endothelium plays an important role in facilitating the pathogenesis of severe malaria.

The endothelial glycocalyx is an important part of the vascular barrier. The glycocalyx is intimately linked to the homoeostatic functions of the endothelium. Damage to the glycocalyx precedes vascular pathology. In the first part of this paper, we have reviewed the structure, physiology and pathology of the endothelial glycocalyx, based on a literature search of the past five years. In the second part, we have systematically reviewed interventions to protect or repair the glycocalyx. Glycocalyx damage can be caused by hypervolaemia and hyperglycaemia and can be prevented by maintaining a physiological concentration of plasma protein, particularly albumin. Other interventions have been investigated in animal models: these require clinical research before their introduction into medical practice.

The endothelial glycocalyx is an extracellular matrix that coats the endothelium and extends into the lumen of blood vessels, acting as a barrier between the vascular wall and blood flowing through the vessel. This positioning of the glycocalyx permits a variety of its constituents, including the major endothelial proteoglycans glypican-1 and syndecan-1, as well as the major glycosaminoglycans heparan sulfate and hyaluronic acid, to contribute to the processes of mechanosensation and subsequent mechanotransduction following such stimuli as elevated shear stress. To coordinate the vast array of processes that occur in response to physical force, the glycocalyx interacts with a plethora of membrane and cytoskeletal proteins to carry out specific signaling pathways resulting in a variety of responses of endothelial cells and, ultimately, blood vessels to mechanical force. This review focuses on proposed glycocalyx-protein relationships whereby the endothelial glycocalyx interacts with a variety of membrane and cytoskeletal proteins to transduce force into a myriad of chemical signaling pathways. The established and proposed interactions at the molecular level are discussed in context of how the glycocalyx regulates membrane/cytoskeletal protein function in the many processes of endothelial mechanotransduction.

The negatively charged, brush-like glycocalyx covers the surface layer of endothelial cells. This layer of membrane-bound, carbohydrate-rich molecules covers the luminal surface of the endothelium along the entire vascular tree, mostly comprising glycoproteins and proteoglycans. Together with the underlying actin-rich endothelial cortex, 50 to 150 nm beneath the plasma membrane, the endothelial glycocalyx (eGC) is recognized as a vasoprotective nanobarrier and responsive hub. Importantly, both the eGC and cortex are highly dynamic and can adapt their nanomechanical properties (ie, stiffness and height) to changes in the environment. The constant change between a soft and a stiff endothelial surface is imperative for proper functioning of the endothelium. This review defines the nanomechanical properties of the eGC and stresses the underlying mechanisms and factors leading to a disturbed structure-function relationship. Specifically, under inflammatory conditions, the eGC is damaged, resulting in enhanced vascular permeability, tissue edema, augmented leukocyte adhesion, platelet aggregation, and dysregulated vasodilation. An integrated knowledge of the relationship between the nanomechanical properties, structure, and function of the eGC might be key in understanding vascular function and dysfunction. In this context, the clinical aspects for preservation and restoration of proper eGC nanomechanics are discussed, considering the eGC as a potentially promising diagnostic marker and therapeutic target in the near future.

All cells in the human body are covered by a complex meshwork of sugars as well as proteins and lipids to which these sugars are attached, collectively termed the glycocalyx. Over the past few decades, the glycocalyx has been implicated in a range of vital cellular processes in health and disease. Therefore, it has attracted considerable interest as a therapeutic target. Considering its omnipresence and its relevance for various areas of cell biology, the glycocalyx should be a versatile platform for therapeutic intervention, however, the full potential of the glycocalyx as therapeutic target is yet to unfold. This might be attributable to the fact that glycocalyx alterations are currently discussed mainly in the context of specific diseases. In this perspective review, we shift the attention away from a disease-centered view of the glycocalyx, focusing on changes in glycocalyx state. Furthermore, we survey important glycocalyx-targeted drugs currently available and finally discuss future steps. We hope that this approach will inspire a unified, holistic view of the glycocalyx in disease, helping to stimulate novel glycocalyx-targeted therapy strategies.

INTRODUCTION:Surgical treatment is associated with an unwanted response of the organism to the so-called surgical trauma. This response is called surgical stress. Ischaemia-reperfusion injury is one of essential causes of tissue damage. It comprises functional and structural changes in tissue that occur after the restoration of circulation, after an episode of ischaemia. Necrosis of irreversibly changed cells and endothelial and mitochondrial-induced tissue swelling occur. METHODS:Physiology, pathophysiology of endothelial glycocalyx: Endothelial glycocalyx is a 0.2 to 5 micrometres thin heteropolysaccharide layer that covers the endothelium on its intraluminal side. Backbone molecules of the glycocalyx include proteoglycans, glycoproteins, and glycosaminoglycans. Damage of the endothelial glycocalyx was described in trauma patients, in patients with septic shock, in ischemia and reperfusion injury, and during extensive surgical procedures. Approaches to prevent endothelial glycocalyx damage: Remote ischemic preconditioning was tested as a method of ischemia and reperfusion injury prevention during and after surgery. Nevertheless, the expected effect was not confirmed in performed meta-analyses. Endothelial glycocalyx damage can be prevented pharmacologically with a broad spectrum of substances, such as antithrombin III, doxycycline, hydrocortisone, etanercept, or nitric oxide donors. Hydrogen inhalation or albumin affects glycocalyx positively. Sulodexide provides a positive effect on the protection and reparation of endothelial glycocalyx. This proteoglycan with antithrombotic, fibrinolytic, hypofibrinogenemic, and lipolytic function is used for the treatment of venous diseases, ischaemic heart disease, and peripheral arterial disease. A positive effect of sulodexide on renal dysfunction was documented in a model of ischaemia and reperfusion injury. Equally, a positive effect of sulodexide was described on endothelium repair after its mechanical damage. CONCLUSION:Further research needs to be performed to evaluate the effect of endothelium-protectives on glycocalyx damage prevention and repair in ischaemia and reperfusion models involving large laboratory animals or in clinical trials in patients undergoing surgical revascularisation procedures.

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.

BACKGROUND:The number of studies measuring breakdown products of the glycocalyx in plasma has increased rapidly during the past decade. The purpose of the present systematic review was to assess the current knowledge concerning the association between plasma concentrations of glycocalyx components and structural assessment of the endothelium. METHODS:We performed a literature review of Pubmed to determine which glycocalyx components change in a wide variety of human diseases and conditions. We also searched for evidence of a relationship between plasma concentrations and the thickness of the endothelial glycocalyx layer as obtained by imaging methods. RESULTS:Out of 3,454 publications, we identified 228 that met our inclusion criteria. The vast majority demonstrate an increase in plasma glycocalyx products. Sepsis and trauma are most frequently studied, and comprise approximately 40 publications. They usually report 3-4-foldt increased levels of glycocalyx degradation products, most commonly of syndecan-1. Surgery shows a variable picture. Cardiac surgery and transplantations are most likely to involve elevations of glycocalyx degradation products. Structural assessment using imaging methods show thinning of the endothelial glycocalyx layer in cardiovascular conditions and during major surgery, but thinning does not always correlate with the plasma concentrations of glycocalyx products. The few structural assessments performed do not currently support that capillary permeability is increased when the plasma levels of glycocalyx fragments in plasma are increased. CONCLUSIONS:Shedding of glycocalyx components is a ubiquitous process that occurs during both acute and chronic inflammation with no sensitivity or specificity for a specific disease or condition.

Three types of capillaries, namely continuous, fenestrated, and sinusoidal, form the microvascular system; each type has a specialized structure and function to respond to the demands of the organs they supply. The endothelial glycocalyx, a gel-like layer of glycoproteins that covers the luminal surface of the capillary endothelium, is also thought to maintain organ and vascular homeostasis by exhibiting different morphologies based on the functions of the organs and capillaries in which it is found. Recent advances in analytical technology have enabled more detailed observations of the endothelial glycocalyx, revealing that it indeed differs in structure across various organs. Furthermore, differences in the lectin staining patterns suggest the presence of different endothelial glycocalyx components across various organs. Interestingly, injury to the endothelial glycocalyx due to various pathologic and physiological stimuli causes the release of these components into the blood. Thus, circulating glycocalyx components may be useful biomarkers of organ dysfunction and disease severity. Moreover, a recent study suggested that chronic injury to the glycocalyx reduces the production of these glycocalyx components and changes their structure, leading it to become more vulnerable to external stimuli. In this review, we have summarized the various endothelial glycocalyx structures and their functions.

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.

The endothelial glycocalyx is a dynamic surface layer composed of proteoglycans, glycoproteins, and glycosaminoglycans with a key role in maintaining endothelial cell homeostasis. Its functions include the regulation of endothelial barrier permeability and stability, the transduction of mechanical forces from the vascular lumen to the vessel walls, serving as a binding site to multiple growth factors and vasoactive agents, and mediating the binding of platelets and the migration of leukocytes during an inflammatory response. Many of these processes are associated with changes in intracellular calcium levels that may occur through mechanisms that alter calcium entry in the endothelium or the release of calcium from the endoplasmic reticulum. Whether the endothelial glycocalyx can regulate calcium dynamics in endothelial cells is unresolved. Interestingly, during cardiovascular disease progression, changes in calcium dynamics are observed in association with the degradation of the glycocalyx and with changes in barrier permeability and vascular reactivity. Herein, we aim to provide a summarized overview of what is known regarding the role of the glycocalyx as a regulator of endothelial barrier and vascular reactivity during homeostatic and pathological conditions and to provide a perspective on how such processes may relate to calcium dynamics in endothelial cells, exploring a possible connection between components of the glycocalyx and calcium-sensitive pathways in the endothelium.

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.

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.