Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases

Abstract

The endothelial glycocalyx has a profound influence at the vascular wall on the transmission of shear stress, on the maintenance of a selective permeability barrier and a low hydraulic conductivity, and on attenuating firm adhesion of blood leukocytes and platelets. Major constituents of the glycocalyx, including syndecans, heparan sulphates and hyaluronan, are shed from the endothelial surface under various acute and chronic clinical conditions, the best characterized being ischaemia and hypoxia, sepsis and inflammation, atherosclerosis, diabetes, renal disease and haemorrhagic viral infections. Damage has also been detected by in vivo microscopic techniques. Matrix metalloproteases may shed syndecans and heparanase, released from activated mast cells, cleaves heparan sulphates from core proteins. According to new data, not only hyaluronidase but also the serine proteases thrombin, elastase, proteinase 3 and plasminogen, as well as cathepsin B lead to loss of hyaluronan from the endothelial surface layer, suggesting a wide array of potentially destructive conditions. Appropriately, pharmacological agents such as inhibitors of inflammation, antithrombin and inhibitors of metalloproteases display potential to attenuate shedding of the glycocalyx in various experimental models. Also, plasma components, especially albumin, stabilize the glycocalyx and contribute to the endothelial surface layer. Though symptoms of the above listed diseases and conditions correlate with sequelae expected from disturbance of the endothelial glycocalyx (oedema, inflammation, leukocyte and platelet adhesion, low reflow), therapeutic studies to prove a causal connection have yet to be designed. With respect to studies on humans, some clinical evidence exists for benefits from application of sulodexide, a preparation delivering precursors of the glycocalyx constituent heparan sulphate. At present, the simplest option for protecting the glycocalyx seems to be to ensure an adequate level of albumin. However, also in this case, definite proof of causality needs to be delivered.

Keywords: diabetes; inflammation; ischaemia; protease; renal failure; sepsis.

© 2015 The British Pharmacological Society.

Figures

Figure 1

Electron microscopic view of a human mammary artery (end piece not utilized for coronary bypass grafting) after fixation with lanthanium(III)nitrate/glutaraldehyde solution. The thickness of the glycocalyx (dark fibrous zone) is approximately 200 nm. For details, see [7,28]

Figure 2

Light-microscopic picture of a slice of human placenta stained with antibody against syndecan-1 (brown stain). There is intense colouration at the villous surface, i.e. the interface between maternal blood and fetal tissue, but none in the fetal capillaries. For details, see [44]

Figure 3

Schematic illustration of the endothelial surface layer in the presence of albumin (red dots), negatively charged at physiological plasma pH. The negative charges on heparan, chondroitin and dermatan sulphate glycosaminoglycan side chains of proteoglycans of the glycocalyx attract cations, especially the divalent Ca-ions, which shield the sulphate groups. Out of purely electrostatic considerations, this may provide an electrical double layer with a positively charged ‘outer’ face, to which albumin molecules will be attracted. Binding and enrichment of albumin in the glycocalyx results, a feature lacking for the artificial colloids in present day clinical use (all uncharged at physiological pH). For reasons of simplicity, Na+, K+ and Mg2+ ions are not included in the scheme

Figure 4

Light microscopic picture of a slice of guinea pig heart perfused with a bolus of 3 × 106 human polymorphonuclear neutrophilic granulocytes, prestimulated with formyl-Meth-Leu-Phe. The heart was fixation-perfused with formalin, sliced and stained with antibody against human elastase. The brown colouration identifies elastase in granules within a PMN attached to the wall of a small venule and beginning to spread out along the endothelial surface. For details, see [26,134]