Glycocalyx and its involvement in clinical pathophysiologies
© The Author(s). 2016
Received: 19 April 2016
Accepted: 22 August 2016
Published: 8 September 2016
Vascular hyperpermeability is a frequent intractable feature involved in a wide range of diseases in the intensive care unit. The glycocalyx (GCX) seemingly plays a key role to control vascular permeability. The GCX has attracted the attention of clinicians working on vascular permeability involving angiopathies, and several clinical approaches to examine the involvement of the GCX have been attempted. The GCX is a major constituent of the endothelial surface layer (ESL), which covers most of the surface of the endothelial cells and reduces the access of cellular and macromolecular components of the blood to the surface of the endothelium. It has become evident that this structure is not just a barrier for vascular permeability but contributes to various functions including signal sensing and transmission to the endothelium. Because GCX is a highly fragile and unstable layer, the image had been only obtained by conventional transmission electron microscopy. Recently, advanced microscopy techniques have enabled direct visualization of the GCX in vivo, most of which use fluorescent-labeled lectins that bind to specific disaccharide moieties of glycosaminoglycan (GAG) chains. Fluorescent-labeled solutes also enabled to demonstrate vascular leakage under the in vivo microscope. Thus, functional analysis of GCX is advancing. A biomarker of GCX degradation has been clinically applied as a marker of vascular damage caused by surgery. Fragments of the GCX, such as syndecan-1 and/or hyaluronan (HA), have been examined, and their validity is now being examined. It is expected that GCX fragments can be a reliable diagnostic or prognostic indicator in various pathological conditions. Since GCX degradation is strongly correlated with disease progression, pharmacological intervention to prevent GCX degradation has been widely considered. HA and other GAGs are candidates to repair GCX; further studies are needed to establish pharmacological intervention. Recent advancement of GCX research has demonstrated that vascular permeability is not regulated by simple Starling’s law. Biological regulation of vascular permeability by GCX opens the way to develop medical intervention to control vascular permeability in critical care patients.
KeywordsGlycocalyx Vascular permeability Starling’s law Endothelial surface layer Hyaluronan Heparan sulfate Syndecan-1 Sepsis Lectin Leukocyte
More than 70 years ago, Danielli  and Chambers and Zweifach  introduced the concept of a thin non-cellular layer on the endothelial surface. This layer was thought to include absorbed plasma protein, although a direct demonstration of this layer was technically impossible at that time. About 20 years later, Copley  reported the endothelium–plasma interface and developed a concept in which the endothelial surface was covered by a thin molecular layer and an immobile sheet of plasma. The existence of the latter structure was identified when intravital microscopy was used to examine the hamster cheek pouch. In 1966, Luft used ruthenium red staining and electron microscopy to examine the endothelial surface . Using this technique, Luft directly demonstrated the existence of an endocapillary layer that had evaded visualization using light or electron microscopy; this layer had a thickness in the range of 20 nm. Subsequent studies replicated these results and led to the concept that this layer was composed of proteoglycans (PGs) and glycosaminoglycans (GAGs) with a thickness of several tens of nanometers, as has been previously reviewed [5, 6]. Since the 1970s, the development of the intravital model for studying microcirculation has enabled several indirect and direct observations of the existence of an endothelial surface layer with a gel-like endothelial glycocalyx layer (GCX) located on the luminal surface of blood vessels .
Biology of glycocalyx
Structure of the endothelial GCX
Characterization of proteoglycan core proteins in glycocalyx
Core size (kDa)
Number of subtype
The composition and dimensions of the GCX fluctuate as it continuously replaces material sheared by flowing plasma , while throughout the vasculature, the thickness varies tenfold from several hundreds of nanometers to several micrometers . The GCX forms a luminal mesh that provides endothelial cells with a framework to bind plasma proteins and soluble GAGs [16, 17].
Physiological function of the ESL
Vascular permeability barrier
The ESL and the GCX regulate vascular permeability . The charged and complexed mesh structure of the GCX acts as a macromolecular sieve , repelling negatively charged molecules as well as white and red blood cells and platelets. For example, macromolecules larger than 70 kDa are known to be excluded from the GCX. Albumin is 67 kDa and has a net negative charge but binds tightly to the GCX  because of its amphoteric nature (it carries some positive charges along the protein chain). This binding reduces the hydraulic conductivity across the vascular barrier; therefore, some albumin leaks through the GCX . Some pathophysiological statuses that are accompanied by the disruption of the GCX can lead to hyperpermeability.
The GCX also acts as a mechanotransducer, transmitting shear stress forces to endothelial cells thorough its intracellular protein domain [8, 18]. Conformational changes in the GCX, which can be induced by blood flow, trigger the release of nitric oxide, thereby contributing to the regulation of vasomotor tone and the peripheral distribution of oxygen. The GCX thus contributes to the maintenance of homeostasis in the peripheral tissues through this rheological mechanism .
Vascular protection via the inhibition of coagulation and leukocyte adhesion
The GCX has been shown to be a significant binding site for blood proteins, such as antithrombin III, fibroblast growth factor, and extracellular superoxide dismutase. Based on these interactions, the most important physiological role of the endothelial GCX is vascular protection via the inhibition of coagulation and leucocyte adhesion [21, 22].
Cell adhesion molecules on the endothelium, such as integrins and immunoglobulins, are buried deep within the ESL. Under inflammatory conditions, the activation and/or externalization of proteases or glycosidases can lead to the degradation of the GCX through the digestion of PGs and/or GAGs. Shedding of the GCX may facilitate ligand-receptor interactions that promote the adhesion of leukocytes .
Ultrastructure observation by electron microscopy
Visualization by intravital microscopy
Direct visualization of the GCX can be performed using several approaches, most of which use fluorescent-labeled lectins that bind to specific disaccharide moieties of GAG chains .
It has been examined a variety of fluorescent-labeled lectins for visualizing the ESL in vivo using fluorescence microscopy and shown that the specific binding of FITC (fluorescein isothiocyanate)-labeled WGA (wheat germ agglutinin) to the luminal surface of the vessel could be appropriately monitored in a mouse dorsal skinfold window [30, 31].
Recently, a novel technique that directly visualizes larger vessels using a two-photon laser scanning microscope (TPLSM) enabled a detailed description of the endothelial surface and the identification of the GCX [32, 33] because of its enhanced penetration depth, good resolution, and optical sectioning. It has been reported that thickness of the GCX of intact mouse carotid arteries was 4.5 μm by means of this technique .
The heparanase-mediated mice also lose the ESL, which leads to the exposure of ICAM-1, VCAM-1 to circulating activated neutrophils, facilitating their adherence and extravasation [22, 37, 38]. Increases in the expressions of E-selectin, ICAM-1, and VCAM-1 have been reported in human microvascular endothelial cells [39, 40] and mice . Although the importance of the GCX is being recognized, further study is needed to clarify the integrated mechanisms involved in the loss of the GCX and leukocyte-endothelium interactions.
Another functional role of the GCX is as a barrier to vascular permeability. To observe changes in vascular permeability in vivo, a dye extraction method, such as the Evans blue method, has been used . However, with the development of fluorescent imaging, the use of dextran covalently linked to a fluorophore has become the standard technique for qualifying and quantifying vascular permeability. In some studies, FITC-labeled bovine serum albumin (BSA; molecular weight, 66 kDa) has been used to determine the vascular permeability in rodent chamber models. As a substitute for BSA, dextran, a molecular weight of 70 kDa has also been used extensively, since it has a similar molecular weight. In a study performed by Alfieri , they used FITC albumin, and its leakage was quantified by using the alteration of fluorescence in the ROIs (region of interests) consisted of defined squares of 900 μm2 (30 × 30 μm) located in three distinct interstitial areas. This technique can be applied to various weights of molecules. Kataoka and colleagues modified this method; FITC-labeled dextran (70 kDa) was injected intravenously in the mouse model, and the fluorescent intensity in ROIs (30 × 30 μm; Fig. 3b) using intravital microscopy was monitored. The data enabled the quantitative and continuous analysis of permeability under septic conditions (Kataoka et al., submitted).
Pathophysiologies involving the GCX
Revised Starling’s law
The GCX layer and its mechanism for controlling fluid movement
The GCX covers the luminal surface of the endothelium, which sieves molecules to the interstitium. The sub-GCX space in the intercellular cleft also forms a buffer space for molecules from the interstitium and intravascular spaces. This fragile and tiny structure acts as a barrier for the vessels. Studies on microvascular fluid exchange have attempted to estimate the accurate Pc (hydrostatic pressure) and π (osmotic pressure) and have revealed that the sub-GCX π is lower than the interstitial π. This means that the lower π space in the intercellular cleft insulates fluid movement along the osmotic gradient.
GCX degradation and hyperpermeability
The GCX layer rarely allows water leakage through the ETC. However, once the GCX is disrupted, the permeability of the endothelial cells increases dramatically. Hyperpermeability induced by sepsis is a typical example in which GCX damage induces macromolecule leakage. However, the denudation of the vascular inner lumen itself cannot explain the leakage of water and other molecules, since endothelial cells bind tightly with neighboring cells via specific proteins, including cadherin and claudin [46, 47]. Therefore, the mechanism by which GCX degradation results in vascular hyperpermeability needs to be established. There are two pathways for the leakage of water and other molecules. The ETC has been suggested as one possible pathway and has been named the paracellular pathway . This pathway requires the opening of intercellular keys, the proteins of which are known as tight junctions, adherent junctions, and gap junctions. This pathway seems to require intracellular signal conduction to loosen these junctions. A transcellular pathway has also been suggested. Vesicular transport to the interstitium has been confirmed during sepsis. The transcellular transport of macromolecules also results in interstitial edema.
GCX and vascular contraction
The GCX has been shown to sense blood flow and to regulate vascular tone via the production of NO (nitric oxide).
Yen et al. demonstrated that the denudation of the GCX by heparinase III reduced NO production; thus, the GCX has a physiological role in mechanosensing [48, 49], which may have an important role in the development of angiopathies and arteriosclerosis. According to the proposed hypothesis, GAGs holds negatively charged HS and consists of the structured water area. This area excludes the blood stream and protects the endothelial surface from being damaged. Positively charged cells or substances streaming in a column of negative charges create an electromagnetic field, resulting in the production of NO . NO physiologically dilates vessels; if the dilation is sustained pathologically, NO further triggers free radicals and disrupts the ESL . This disruption was suggested to trigger cholesterol accumulation, resulting in arteriosclerosis. Since the GCX is an insulator, this hypothesis is convincing. Further study may unveil the mechanism responsible for vascular aging, which would promote additional investigations of the GCX.
Clinical monitoring of the GCX
Angiopathy is a frequent pathological feature involved in a wide range of diseases. The GCX has attracted the attention of clinicians working on angiopathies, and several clinical approaches to examining the involvement of the GCX have been attempted. A biomarker of GCX degradation has been clinically applied as a marker of vascular damage caused by surgery. Fragments of the GCX, such as syndecan-1 and/or hyaluronan (HA), have been examined, and their validity is now being examined. Various clinical studies have also been reported.
Clinical assessments of GCX damage
Soluble VEGF receptor 1
Positive correlation with injury severity
Syn-1, HA, sFlt-1, sVCAM-1, vWF, angiopoietin-2
Syn-1, HA increased in parallel with CKD stage
Syn-1, slCAM-1, sVE-cadherin, hyaluronan
Slight increase in syn-1 at 24 h after transfusion
Syn-1, slCAM-1, sVE-cadherin, hyaluronan
High syn-1 was associated with bleeding, impaired platelet function
Acute decompensated heart failure
Syn-1 was high in AKI
Disease activity was correlated with syn-1
Page  (review)
Ang-1,-2, vWF, thrombomodulin, sE-selectin, slCAM-1, sVCAM-1
A biomarker with consistent clinical utility was not identified
Children, diabetes mellitus type 1
GCX thickness was inversely correlated with glucose
Pulsatile and non-pulsatile reduced perfusion density zone
Diabetes mellitus type 2
Sulodexide increased GCX thickness
The GCX covers various receptors on the endothelial surface. Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis as well as permeability and vasodilation. This factor binds two types of receptors: VEGFR1 and VEGFR2. The binding of these receptors is regulated by soluble Fms-like tyrosine kinase receptor (sFlt-1). Reportedly, elevations in sFlt-1 are closely correlated with the APACHE II (Acute Physiology and Chronic Health Evaluation II) score, and the sFlt-1 level might be useful as a predictor of survival . This receptor fragment on the endothelial surface is conceivably induced by GCX degradation. Actually, a close association has been shown between an elevation in syndecan-1 and the sVEGFR1 level (r = 0.76, P < 0.001) . The appearance of this receptor fragment in the blood may reflect the extent of GCX degradation.
Pharmacological preservation and intervention
Pharmacological intervention for GCX protection
Diabetes mellitus type 2
GCX thickness increased
Improved intestinal perfusion
Attenuation of Syn-1 and HA release
Immobilized heparin conjugate
Attenuation of thrombotic disorder
Isolated mouse lung
HES attenuated interstitial edema, increased pulmonary arterial pressure
Isolated guinea pig heart
Increase in Syn-1 and reduction in HS
Isolated guinea pig heart
Increase in Syn-1 and reduction in HS
Hydroxyethyl starch has been reported to prevent capillary leakage , and its mechanism is assumed to have a plugging effect on ESL pores caused by GCX degradation [74, 75]. Whether the mechanism involves plugging or a specific interaction with the GCX remains uncertain .
Hydrocortisone is expected to reduce GCX damage ; this result has been obtained in an animal model, which also exhibited a reduction in sydecan-1 release, and tissue edema. Further experiments have shown that this mechanism involves the prevention of IRI-induced platelet adhesion [77, 78]. Sevoflurane also has a protective effect on the GCX by preventing IRI-induced leukocyte and platelet adhesion [79, 80].
Atrial natriuretic hormone (ANP) is assumed to cause the GCX shedding. ANP is excreted from the atrium and plays a role in regulating the intravascular volume. Physiological levels of this peptide have been shown to result in the GCX shedding and the promotion of vascular leakage . Hypervolemia itself triggers ANP excretion. Since hypervolemia is harmful to thin layers, such as in the lung or other organs, excessive water should be drained. ANP may act to open water channels to the interstitium, resulting in the efflux of water . Whether ANP is a regulator of the strength of the GCX seal or the disruption of the GCX is uncertain. In this context, matrix metalloprotease has been experimentally shown to reduce GCX damage. This pathway has also attracted attention in terms of protecting the GCX.
Although pharmacological intervention to GCX is widely challenged, the physiological synthesis and turn-over has not been elucidated. There may be a key point to preserve and protect GCX from various kind of injury. Albumin has been shown to reduce GCX shedding caused by cold ischemia . Also fresh frozen plasma (FFP) has been shown to protect vascular endothelial permeability . GCX layer is coated by albumin and proteins; thus, these natural components may not only constitute the barrier against flowing substances but may nourish GCX. Schött et al. hypothesize that FFP may inhibit or neutralize sheddases (a diverse group of proteases) and/or that FFP mobilizes intracellular stores of preformed syndecans . Further research to elucidate natural turn-over of GCX may disclose the theoretical protection of GCX.
The GCX is an extracellular matrix that covers the luminal surface of the vascular system. This structure is not just a barrier for vascular permeability but contributes to various functions including signal sensing and transmission to the endothelium. Thus, pathological changes to this structure are involved in the development of various diseases. Further research on the GCX is expected to provide useful information for the regulation of vascular-related pathophysiologies.
Acute decompensated heart failure
Atrial natriuretic hormone
Bovine serum albumin
Endothelial surface layer
Fresh frozen plasma
Transmission electron microscopy
Two-photon laser scanning microscope
Vascular endothelial growth factor
We use no specific funding for writing this review.
Availability of data and materials
Since this article is a review article, the datasets supporting the conclusions are available in publicly published articles listed in the reference list.
TI conceived, planned, and organized the manuscript. AU drafted the “Biology of glycocalyx” section, HK drafted the “Research methods” section, and TI drafted the “Pathophysiologies involving the GCX” section. All authors critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
Since this article is a review article, this section is not applicable to this article. We do not include any specific data originally derived from our unpublished experiments or clinical study.
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