Endothelial Glycocalyx Dysfunction Research Articles

Insights into the Molecular Mechanism of Endothelial Glycocalyx Dysfunction during Heart Surgery.

The endothelial glycocalyx (EGC) is a layer of proteoglycans (associated with glycosaminoglycans) and glycoproteins, which adsorbs plasma proteins on the luminal surface of endothelial cells. Its main function is to participate in separating the circulating blood from the inner layers of the vessels and the surrounding tissues. Physiologically, the EGC stimulates mechanotransduction, the endothelial charge, thrombocyte adhesion, leukocyte tissue recruitment, and molecule extravasation. Hence, severe impairment of the EGC has been implicated in various pathological conditions, including sepsis, diabetes, chronic kidney disease, inflammatory disorders, hypernatremia, hypervolemia, atherosclerosis, and ischemia/reperfusion injury. Moreover, alterations in EGC have been associated with altered responses to therapeutic interventions in conditions such as cardiovascular diseases. Investigation into the function of the glycocalyx has expanded knowledge about vascular disorders and indicated the need to consider new approaches in the treatment of severe endothelial dysfunction. This review aims to present the current understanding of the molecular mechanisms underlying cardiovascular diseases and to elucidate the impact of heart surgery on EGC dysfunction.

Investigation of the relationship between intradialytic hypotension during hemodialysis and serum syndecan-1 concentration

Intradialytic hypotension and arrhythmias are complications of hemodialysis. They are associated with decreased intravascular volume due to reduced ultrafiltration volume, cardiac function, and arterial tone. The vascular endothelial glycocalyx, which exists on the surface of healthy vascular endothelial cells and maintains vascular permeability, has been suggested to be impaired by hemodialysis. This single-center retrospective study evaluated the association between syndecan-1, an endothelial glycocalyx dysfunction marker, and complications of hemodialysis. We enrolled 92 patients who underwent outpatient hemodialysis at Gifu Seiryu Hospital from April to July 2022 (346 hemodialysis sessions). The median duration and time of hemodialysis were 40 months and 4.1 h, respectively. Median serum syndecan-1 levels were 67.7 ng/mL before and 98.3 ng/mL after hemodialysis. Hemodialysis complications were noted in 68 sessions, all of which were hypotension. No correlation between pre-hemodialysis syndecan-1 levels and the incidence of complications was observed. However, a positive correlation between the amount of change in syndecan-1 levels before and after hemodialysis and the incidence of hemodialysis complications was noted. Conversely, syndecan-1 levels did not correlate with brain or atrial natriuretic peptides, suggesting that impairment of the vascular endothelial glycocalyx may be a possible cause of intradialytic hypotension and may be useful in preventing intradialytic hypotension.

The Endothelial Glycocalyx and Neonatal Sepsis.

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.

Arterial hypertension as a consequence of endothelial glycocalyx dysfunction: a modern view of the problem of cardiovascular diseases

Arterial hypertension (AH) is a leading risk factor for the development of cardiovascular, cerebrovascular, and renal diseases, which are among the top 10 most common causes of death in the world. The etiology of hypertension has not been fully elucidated, but it has been established that endothelial dysfunction is the most significant pathogenetic link in the formation and progression of the disease. The data obtained in the last 10-15 years on endothelial glycocalyx (eGC) studies indicate that endothelial dysfunction is preceded by destabilization and shedding of eGC with the appearance of its soluble components in the blood, which is equivalent to a process that can be designated as eGC dysfunction. Signs of eGC dysfunction are expressed in the development of hypertension, diseases of the cardiovascular system, and their complications. The purpose of this review is to analyze and substantiate the pathophysiological role of eGC dysfunction in hypertension and cardiovascular diseases and to describe approaches for its assessment and pharmacological correction. Abstracts and full-size articles of 425 publications in Pubmed/MEDLINE databases over 20 years were studied. The review discusses the role of eGC in the regulation of vascular tone, endothelial barrier function, and anti-adhesive properties of eGC. Modifications of eGC under the influence of pro-inflammatory stimuli, changes in eGC with age, and with increased salt load are considered. The aspect associated with eGC dysfunction in atherosclerosis, hyperglycemia and hypertension is covered. Assessment of eGC dysfunction is difficult but can be performed by indirect methods, in particular by detecting eGC components in blood. A brief description of the main approaches to pharmacoprevention and pharmacocorrection of hypertension is given from the position of exposure effects on eGC, which currently has more a fundamental than practical orientation. This opens up great opportunities for clinical studies of eGC dysfunction for the prevention and treatment of hypertension and justifies a new direction in the clinical pharmacology of antihypertensive drugs.

Markers of endothelial glycocalyx dysfunction in Clarkson disease

BackgroundClarkson disease (monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome, ISCLS) is a rare idiopathic condition marked by transient, relapsing-remitting episodes of systemic microvascular hyper-permeability, which liberates plasma fluid and macromolecules into the peripheral tissues. This pathology manifests clinically as the abrupt onset of hypotensive shock, hemoconcentration, and hypoalbuminemia.MethodsWe analysed endothelial glycocalyx (eGCX)-related markers in plasma from patients with ISCLS during acute disease flares and convalescence by ELISA and comprehensive proteomic profiling. We evaluated eGCX-related components and gene expression in cultured endothelial cells using RNA-sequencing, real-time PCR, and fluorescence staining.ResultsSerum levels of eGCX-related core components including hyaluronic acid (HA) and the core proteoglycan soluble syndecan-1 (sCD138) were elevated at baseline and during acute ISCLS flares. Serial measurements demonstrated that sCD138 levels peaked during the recovery (post-leak) phase of the illness. Proteomic analysis of matched acute and convalescent ISCLS plasma revealed increased abundance of eGCX-related proteins, including glypicans, thrombospondin-1 (TSP-1), and eGCX-degrading enzymes in acute compared to remission plasma. Abundance of endothelial cell damage markers did not differ in acute and baseline plasma. Expression of several eGCX-related genes and surface carbohydrate content in endothelial cells from patients with ISCLS did not differ significantly from that observed in healthy control cells.ConclusionseGCX dysfunction, but not endothelial injury, may contribute to clinical symptoms of acute ISCLS.Serum levels of of eGCX components including sCD138 may be measured during acute episodes of ISCLS to monitor clinical status and therapeutic responses.

The SARS-CoV-2/Receptor Axis in Heart and Blood Vessels: A Crisp Update on COVID-19 Disease with Cardiovascular Complications.

The SARS-CoV-2 virus causing COVID-19 disease has emerged expeditiously in the world and has been declared pandemic since March 2020, by World Health Organization (WHO). The destructive effects of SARS-CoV-2 infection are increased among the patients with pre-existing chronic conditions and, in particular, this review focuses on patients with underlying cardiovascular complications. The expression pattern and potential functions of SARS-CoV-2 binding receptors and the attributes of SARS-CoV-2 virus tropism in a physio-pathological state of heart and blood vessel are precisely described. Of note, the atheroprotective role of ACE2 receptors is reviewed. A detailed description of the possible detrimental role of SARS-CoV-2 infection in terms of vascular leakage, including endothelial glycocalyx dysfunction and bradykinin 1 receptor stimulation is concisely stated. Furthermore, the potential molecular mechanisms underlying SARS-CoV-2 induced clot formation in association with host defense components, including activation of FXIIa, complements and platelets, endothelial dysfunction, immune cell responses with cytokine-mediated action are well elaborated. Moreover, a brief clinical update on patient with COVID-19 disease with underlying cardiovascular complications and those who had new onset of cardiovascular complications post-COVID-19 disease was also discussed. Taken together, this review provides an overview of the mechanistic aspects of SARS-CoV-2 induced devastating effects, in vital organs such as the heart and vessels.

Fluid management in chronic kidney disease: what is too much, what is the distribution, and how to manage fluid overload in patients with chronic kidney disease?

Assessment of fluid status to reach normovolemia in patients with chronic kidney disease (CKD) continues to be a tough task. Besides clinical observation, technological methods have been introduced, yet, the best approach is still uncertain. The present review looks at fluid overload in CKD from three perspectives: the critical fluid threshold leading to adverse cardiovascular outcomes, fluid distribution and its clinical correlates, and direct effect of fluid overload on vascular function related to disturbance of the sodium-skin axis and endothelial glycocalyx dysfunction. To determine fluid status, both the absolute and relative fluid overload is used as parameter in clinical practice. In addition, the definition of fluid overload is ambivalent and its relation to symptom burden has not been studied well. Studies on the impact of distribution of fluid are scarce and the limited evidence suggests differences based on the cause of CKD. So far, no standardized technologies are available to adequately determine fluid distribution. After discovering the 'third compartment' of total body sodium in skin and muscle tissue and its potential direct effect on vascular function, other biomarkers such as VEGF-C are promising. We propose a multimodal clinical approach for volume management in CKD. Because there are currently no studies are available demonstrating that correction of fluid overload in CKD will lead to better outcome, these are strongly needed.

Sodium-induced inflammation-an invisible player in resistant hypertension.

The purpose of this review was to discuss the role of sodium and inflammation in the pathophysiology of hypertension and the observed different hemodynamic effects of drugs. The Pathway-2 study revealed that similar reductions in vascular resistance after spironolactone and doxazosin resulted in opposite effects on sodium balance, water retention, and hemodynamic parameters. These and other clinical findings were bridged to recent experimental and physiological data. Tissue sodium accumulation in salt-sensitive individuals due to endothelial glycocalyx dysfunction causes macrophage infiltration, vascular inflammation, and local changes in angiotensin-2 and aldosterone concentrations. This inflammatory cascade leads to factor XII-related coagulation disorders with neutrophil extracellular trap formation (NETosis). This model of sodium-induced microcirculation impairment was used to explain the differences in central hemodynamic parameters after spironolactone or doxazosin treatment in resistant hypertension. Hypertension treatment by induced sodium removal or reduced sodium intake should reduce endothelial glycocalyx dysfunction, inflammation, NETosis, and coagulation disorders, leading to improved vascular health and cardiac diastolic function.

Fibroblast growth factor 23, endothelium biomarkers and acute kidney injury in critically-ill patients

BackgroundFibroblast growth factor 23 (FGF23) and endothelium-related biomarkers have been related to AKI in critically-ill patients. Also, FGF23 is associated with endothelial dysfunction. In this study, we investigated if elevated FGF23 association with severe AKI is mediated by several endothelial/glycocalyx-related biomarkers.MethodsProspective cohort study with critically-ill patients. Blood samples were collected within the first 24 h after ICU admission. Severe AKI (defined according to KDIGO stage 2/3) was the analyzed outcome.Results265 patients were enrolled and 82 (30.9%) developed severe AKI—defined according to KDIGO stage 2/3. Blood samples to biomarkers measurement were collected within the first 24 h after ICU admission. After adjustment for several variables, FGF23, vascular cell adhesion protein 1 (VCAM-1), angiopoietin 2 (AGPT2), syndecan-1 and intercellular adhesion molecule-1 (ICAM-1) were associated with severe AKI. The individual indirect effects of VCAM-1, AGPT2 and syndecan-1 explained 23%, 31%, and 32% of the total observed effect of FGF23 on severe AKI, respectively. ICAM-1 showed no statistically significant mediation. When all three endothelium-related biomarkers were included in a directed acyclic graph (DAG), the Bayesian network learning suggested the following causal association pathway FGF-23 → syndecan-1 → VCAM-1 → AGPT2 → severe AKI.ConclusionsThe association between FGF23 and AKI are mediated by endothelium-related biomarkers, mainly VCAM-1, AGPT2 and syndecan-1. Moreover, the statistical models show that syndecan-1, a biomarker of endothelial glycocalyx dysfunction, seems to be the initial mediator between FGF23 and severe AKI.

Ulinastatin attenuates pulmonary endothelial glycocalyx damage and inhibits endothelial heparanase activity in LPS-induced ARDS

Acute respiratory distress syndrome (ARDS) is a syndrome of acute respiratory failure characterized by major pathologic mechanisms of increased microvascular permeability and inflammation. The glycocalyx lines on the endothelial surface, which determines the vascular permeability, and heparanase play pivotal roles in the degradation of heparan sulfate (HS). HS is the major component of the glycocalyx. The aim of this study is to examine the effects of Ulinastatin (UTI) on vascular permeability and pulmonary endothelial glycocalyx dysfunction induced by lipopolysaccharide (LPS). In our study, C57BL/6 mice and human umbilical vein endothelial cells were stimulated with LPS to induce injury models. After 6 h of LPS stimulation, pulmonary pathological changes, pulmonary edema, and vascular permeability were notably attenuated by UTI. UTI inhibited LPS-induced endothelial glycocalyx destruction and significantly decreased the production of HS as determined by ELISA and immunofluorescence. UTI also reduced the active form of heparanase (50 kDa) expression and heparanase activity. Moreover, lysosome pH was investigated because heparanase (65 kDa) can be reduced easily in its active form at 50 kDa in a low pH environment within lysosome. Results showed that UTI could inhibit LPS-induced pH elevation in lysosome. In conclusion, UTI protects pulmonary endothelial glycocalyx integrity and inhibits heparanase activity during LPS-induced ARDS.

Postoperative fluid management.

Postoperative care units are run by an anesthesiologist or a surgeon, or a team formed of both. Management of postoperative fluid therapy should be done considering both patients' status and intraoperative events. Types of the fluids, amount of the fluid given and timing of the administration are the main topics that determine the fluid management strategy. The main goal of fluid resuscitation is to provide adequate tissue perfusion without harming the patient. The endothelial glycocalyx dysfunction and fluid shift to extracellular compartment should be considered wisely. Fluid management must be done based on patient's body fluid status. Patients who are responsive to fluids can benefit from fluid resuscitation, whereas patients who are not fluid responsive are more likely to suffer complications of over-hydration. Therefore, common use of central venous pressure measurement, which is proved to be inefficient to predict fluid responsiveness, should be avoided. Goal directed strategy is the most rational approach to assess the patient and maintain optimum fluid balance. However, accessible and applicable monitoring tools for determining patient's actual fluid need should be further studied and universalized. The debate around colloids and crystalloids should also be considered with goal directed therapies. Advantages and disadvantages of each solution must be evaluated with the patient's specific condition.

The ideal crystalloid – what is ‘balanced’?

This review explores the contemporary definition of the term 'balanced crystalloid' and outlines optimal design features and their underlying rationale. Crystalloid interstitial expansion is unavoidable, but also occurs with colloids when there is endothelial glycocalyx dysfunction. Reduced chloride exposure may lessen kidney dysfunction and injury with a possible mortality benefit. Exact balance from an acid-base perspective is achieved with a crystalloid strong ion difference of 24 mEq/l. This can be done simply by replacing 24 mEq/l of chloride in 0.9% sodium chloride with bicarbonate or organic anion bicarbonate substitutes. Potassium, calcium and magnesium additives are probably unnecessary. Large volumes of mildly hypotonic crystalloids such as lactated Ringer's solution reduce extracellular tonicity in volunteers and increase intracranial pressure in nonbrain-injured experimental animals. A total cation concentration of 154 mmol/l with accompanying anions provides isotonicity. Of the commercial crystalloids, Ringer's acetate solution is close to balanced from both acid-base and tonicity perspectives, and there is little current evidence of acetate toxicity in the context of volume loading, in contrast to renal replacement. The case for balanced crystalloids is growing but unproven. A large randomized controlled trial of balanced crystalloids versus 0.9% sodium chloride is the next step.

The glomerular endothelium emerges as a key player in diabetic nephropathy

The effects of diabetes on glomerular structure and particularly that of the glomerular capillary wall have been extensively documented. By correlation with clinical measurements, Weil and colleagues provide important insights into the functional significance of glomerular structural changes in type 2 diabetes. Podocyte detachment correlates with albumin-to-creatinine ratio, but less strongly than does loss of endothelial fenestrations, which also correlates with reduced glomerular filtration rate. The role of the glomerular endothelium in diabetic nephropathy demands further scrutiny.

P63 Hydrogen sulfide – a novel guardian of the endothelial glycocalyx?

The endothelial glycocalyx occupies substantial space at the luminal surface of the endothelium and serves as protective layer that regulates adhesion of leukocytes to the endothelium. Shedding of the endothelial glycocalyx and increased leukocyte adhesion are common features in inflammatory pathologies pathologies (e.g. ischaemia–reperfusion injury, diabetes) and are mediated in part by ’reactive oxygen species’ (ROS). It has been suggested that H 2 S down-regulates leukocyte adherence via K ATP channels activation on leukocytes and the endothelium as a novel mechanism to limit inflammation. Blood levels of H 2 S are substantially lower in diabetic patients compared to controls suggesting ROS consumption of H 2 S in the diabetic vasculature. However, the role H 2 S in leukocyte adhesion is not understood. We have investigated the effects of GYY4137 in hyperglycaemia (HG) induced endothelial glycocalyx dysfunction and the mechanisms involved in modulation of leukocyte adhesion. Primary bovine retinal endothelial cells (BREC) were exposed to 5.6 mM glucose (NG) and 25 mM glucose (HG) ± GYY4137 (100 μM) for 24 h. Cell based fluorescence assay (CBF) with WGA-FITC was used to study EG changes. Glibenclamide, gliclazide and cromakalim (10 μM) were used to test the role of endothelial K ATP channels in leukostesis. Leukocyte adhesion to BREC was measured in Ibidi perfusion slides (shear stress 1 dyn/cm 2 ). HG-induced endothelial glycocalyx degradation was significantly inhibited by GYY4137 [HG 93 ± 5% vs HG + GYY 107 ± 8%, p < 0.001, n = 12]. Cromakalim, glibenclamide or gliclazide alone had no effect on glycocalyx changes. HG increased leukocyte adhesion was attenuated by GYY4137 [HG 275 ± 1% vs HG GYY 105 ± 11%]. H 2 S driven decrease in leukocyte adhesion was not inhibited by glibenclamide or gliclazide ruling out endothelial K ATP channel activation. H 2 S added simultaneously with HG to BREC pretreated with cromakalim did not affect leukostasis. GYY4137 inhibited HG induced endothelial glycocalyx degradation and leukocyte adhesion highlighting the therapeutic potential for H 2 S donors or the modulation of endogenous H 2 S in preserving endothelial integrity under hyperglycaemic conditions.

Endothelial glycocalyx dysfunction in disease: albuminuria and increased microvascular permeability.

Appreciation of the glomerular microcirculation as a specialized microcirculatory bed, rather than as an entirely separate entity, affords important insights into both glomerular and systemic microvascular pathophysiology. In this review we compare regulation of permeability in systemic and glomerular microcirculations, focusing particularly on the role of the endothelial glycocalyx, and consider the implications for disease processes. The luminal surface of vascular endothelium throughout the body is covered with endothelial glycocalyx, comprising surface-anchored proteoglycans, supplemented with adsorbed soluble proteoglycans, glycosaminoglycans and plasma constituents. In both continuous and fenestrated microvessels, this endothelial glycocalyx provides resistance to the transcapillary escape of water and macromolecules, acting as an integral component of the multilayered barrier provided by the walls of these microvessels (ie acting in concert with clefts or fenestrae across endothelial cell layers, basement membranes and pericytes). Dysfunction of any of these capillary wall components, including the endothelial glycocalyx, can disrupt normal microvascular permeability. Because of its ubiquitous nature, damage to the endothelial glycocalyx alters the permeability of multiple capillary beds: in the glomerulus this is clinically apparent as albuminuria. Generalized damage to the endothelial glycocalyx can therefore manifest as both albuminuria and increased systemic microvascular permeability. This triad of altered endothelial glycocalyx, albuminuria and increased systemic microvascular permeability occurs in a number of important diseases, such as diabetes, with accumulating evidence for a similar phenomenon in ischaemia-reperfusion injury and infectious disease. The detection of albuminuria therefore has implications for the function of the microcirculation as a whole. The importance of the endothelial glycocalyx for other aspects of vascular function/dysfunction, such as mechanotransduction, leukocyte-endothelial interactions and the development of atherosclerosis, indicate that alterations in the endothelial glycocalyx may also be playing a role in the dysfunction of other organs observed in these disease states.