Dermatan sulfate is the predominant antithrombotic glycosaminoglycan in vessel walls: Implications for a possible physiological function of heparin cofactor II

Abstract

The role of different glycosaminoglycan species from the vessel walls as physiological antithrombotic agents remains controversial. To further investigate this aspect we extracted glycosaminoglycans from human thoracic aorta and saphenous vein. The different species were highly purified and their anticoagulant and antithrombotic activities tested by in vitro and in vivo assays. We observed that dermatan sulfate is the major anticoagulant and antithrombotic among the vessel wall glycosaminoglycans while the bulk of heparan sulfate is a poorly sulfated glycosaminoglycan, devoid of anticoagulant and antithrombotic activities. Minor amounts of particular a heparan sulfate (< 5% of the total arterial glycosaminoglycans) with high anticoagulant activity were also observed, as assessed by its retention on an antithrombin-affinity column. Possibly, this anticoagulant heparan sulfate originates from the endothelial cells and may exert a significant physiological role due to its location in the interface between the vessel wall and the blood. In view of these results we discuss a possible balance between the two glycosaminoglycan-dependent anticoagulant pathways present in the vascular wall. One is based on antithrombin activation by the heparan sulfate expressed by the endothelial cells. The other, which may assume special relevance after vascular endothelial injury, is based on heparin cofactor II activation by the dermatan sulfate proteoglycans synthesized by cells from the subendothelial layer.

Inhibition of thrombin generation by dermatan sulfate isolated from the skin of Oreochromis niloticus

“…As the separation by DEAE-cellulose of a complex mixture of sulfated glycans is not always possible (Tovar et al, 2005), our studies further extended to physical-chemically analyze by electrophoretic techniques the degree of purity and molecular mass of the O. niloticus fractions, as illustrated in Figure 1.…”

“…40 kDa) (Figure 1Ba) . Taking to literature data, it was speculated a possible mixture of O. niloticus skin DS and CS, which were not separated by DEAE-cellulose using different ionic strength (Tovar et al, 2005).…”

“…40 kDa) with therapeutic implications in the coagulation, when an increase of plasma prothrombin's referential values increase the TG after activation by both intrinsic and extrinsic pathways (Castoldi & Rosing, 2011). A more detailed analysis regarding its anticoagulant mechanisms is needed as an essential step to antithrombotic drug development (Tovar et al, 2005;Jun et al, 2014;Mourão, 2015).…”

“…They are heteropolysaccharides consisting of repeated units of alternating residues of N-acetylgalactosamine or glycosamine linked to a non-nitrogenated sugar, like uronic acid (D-glycuronic acid or L-iduronic acid) or a galactose, making themselves typical chains are known as mucopolysaccharides, and their association to proteoglycans form the matrix' principal elements playing several physiological and pathological events (Tovar et al, 2005;Volpi, 2011;Oliveira et al, 2015). Chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate and heparin (HEP) are the most GAGs found, varying not only the hexosamine and non-aminated sugar residue but also the degree and position of sulfated groups, as well as the type of glycoside bond.…”

Pharmacology of Heparin and Related Drugs

“…HCII deficiency has no effect on plasma coagulation, but it does give rise to an increase in the formation of occlusive arterial thrombi after damage to the endothelium (He et al, 2002). In vivo HCII is potentiated by dermatan sulfate, which is present in blood vessel walls (Tovar et al, 2005). Dermatan sulfate-activated HCII may therefore play a part in the prevention of excessive thrombosis in vascular injury (Tollefsen, 2010).…”