Endothelial Glycocalyx as a Shield Against Diabetic Vascular Complications

Abstract

The endothelial glycocalyx (EG), which covers the apical surface of the endothelial cells and floats into the lumen of the vessels, is a key player in vascular integrity and cardiovascular homeostasis. The EG is composed of PGs (proteoglycans), glycoproteins, glycolipids, and glycosaminoglycans, in particular hyaluronan (HA). HA seems to be implicated in most of the functions described for EG such as creating a space between blood and the endothelium, controlling vessel permeability, restricting leukocyte and platelet adhesion, and allowing an appropriate endothelial response to flow variation through mechanosensing. The amount of HA in the EG may be regulated by HYAL (hyaluronidase) 1, the most active somatic hyaluronidase. HYAL1 seems enriched in endothelial cells through endocytosis from the bloodstream. The role of the other main somatic hyaluronidase, HYAL2, in the EG is uncertain. Damage to the EG, accompanied by shedding of one or more of its components, is an early sign of various pathologies including diabetes mellitus. Shedding increases the blood or plasma concentration of several EG components, such as HA, heparan sulfate, and syndecan. The plasma levels of these molecules can then be used as sensitive markers of EG degradation. This has been shown in type 1 and type 2 diabetic patients. Recent experimental studies suggest that preserving the size and amount of EG HA in the face of diabetic insults could be a useful novel therapeutic strategy to slow diabetic complications. One way to achieve this goal, as suggested by a murine model of HYAL1 deficiency, may be to inhibit the function of HYAL1. The same approach may succeed in other pathological situations involving endothelial dysfunction and EG damage.

Blocking matrix metalloproteinase-mediated syndecan-4 shedding restores the endothelial glycocalyx and glomerular filtration barrier function in early diabetic kidney disease

“…SDC4 carries HS side chains so HS shedding is likely to accompany SDC4 shedding as we have shown previously in vitro 16 and others have shown in vivo in a diabetes model. 55 Glycocalyx component hyaluronan 56 has also been shown to be shed in diabetes.…”

Principal mode of Syndecan‐4 mechanotransduction for the endothelial glycocalyx is a scissor‐like dimer motion

“…Previous work has shown that endothelial mechanotransduction signalling pathways participate in generation of redox signals that affect inflammation status of cells . However, to this date, the actual intermediate signals of flow‐induced, shear stress–related mechanotransduction have not been elucidated, and the role of EG in this regard is unresolved . What is known is that enzymatic degradation of the EG constituents decreases flow‐induced nitric oxide (a vasoregulating agent responding to shear stress changes) production, confirming that EG plays an important role in such signal transmission.…”

Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

“…Interestingly, this protective coating is very similar to the brain's interstitial extracellular matrix in molecular contents, which is difficult to examine by ultrastructure imaging due to its extreme thinness even at very high magnification due to the tightly packed glia and neurons within a confined space created by the exoskeleton the skull. The elusive ecGCx is in a constant state of flux and also in a constant state of being regenerated and repaired by the endothelium and plasma constituents[63,64,65,66]. The systemic cells and molecules of the blood seldom see or come into direct contact with the plasma membrane-plasmalemma of the EC, because it is constantly and nearly continuously covered by the protective ecGCx surface coating, which prevents direct exposure of systemic blood components to the EC plasma membrane in health.…”