More than a biomarker: the systemic consequences of heparan sulfate fragments released during endothelial surface layer degradation (2017 Grover Conference Series)

Abstract

Advances in tissue fixation and imaging techniques have yielded increasing appreciation for the glycosaminoglycan-rich endothelial glycocalyx and its in vivo manifestation, the endothelial surface layer (ESL). Pathological loss of the ESL during critical illness promotes local endothelial dysfunction and, consequently, organ injury. Glycosaminoglycan fragments, such as heparan sulfate, are released into the plasma of animals and humans after ESL degradation and have thus served as a biomarker of endothelial injury. The development of state-of-the-art glycomic techniques, however, has revealed that these circulating heparan sulfate fragments are capable of influencing growth factor and other signaling pathways distant to the site of ESL injury. This review summarizes the current state of knowledge concerning the local (i.e. endothelial injury) and systemic (i.e. para- or endocrine) consequences of ESL degradation and identifies opportunities for future, novel investigations.

Keywords: glycocalyx; glycosaminoglycans; pulmonary endothelium; sepsis/multiple organ failure.

Fig. 1.

Structure of the endothelial glycocalyx/endothelial surface layer. (a) Endothelial glycocalyx thickness is larger than the endothelial cell itself, as demonstrated by electron microscopy of ruthenium-red labeled rat myocardial capillaries. Figure used with permission from van den Berg et al. Circ Res. In vivo, the glycocalyx forms an even more substantial ESL, with thickness >1 µm. (b) Pathological degradation of the glycocalyx/ESL during critical illnesses (such as sepsis) causes not only local endothelial injury, but also releases biologically active heparan sulfate fragments into the circulation that may influence signaling processes in an endocrine fashion. For simplicity, chondroitin sulfate and hyaluronic acid are not shown. α4 and β4 refer to glycosidic bonds connecting constituent saccharides. Inset: structure of a heparan sulfate octasaccharide fragment, demonstrating potential sites of sulfation within constituent disaccharide units.

Fig. 2.

HS sulfation patterns and catalyzing enzymes. (a) Sulfate groups from the high energy donor, 3’-phosphoadenyl-5’-phosphosulfate (PAP) are transferred to specific positions of HS. Sulfation generally progresses in order as depicted. (b) HS is further modified post-synthetically at cell membrane and extracellular space by sulfatase which specifically cleaves 6-O sulfates from N-glucosamine residues. NDST, N-deacetylase/N-sulfotransferase; HS2ST, heparan sulfate-2-sulfotransferase; HS6ST, heparan sulfate-6-sulfotransferase; HS3ST, heparan sulfate-3-sulfotransferase; α4 and β4: glycosidic bonds.

Fig. 3.

Growth factor signaling may be shaped by both cell-surface and soluble HS. During homeostasis, cell-surface HSPGs provide cis-activation of growth factor signaling by stabilizing ligand-receptor interactions. In the absence of cell-surface HSPGs, this activation may be salvaged by the presence of soluble HS fragments of sufficient size and sulfation to engage growth factor ligands and receptors. In the presence of both cell-surface HSPGs and circulating HS, we hypothesize that the excess of HS sequesters ligands, attenuating downstream growth factor signaling.