Vascular dermatan sulfate regulates the antithrombotic activity of heparin cofactor II.
Heparin cofactor II (HCII)-deficient mice form occlusive thrombi more rapidly than do wild-type mice following injury to the carotid arterial endothelium. Dermatan sulfate (DS) and heparan sulfate (HS) increase the rate of inhibition of thrombin by HCII in vitro, but it is unknown whether vascular glycosaminoglycans play a role in the antithrombotic effect of HCII in vivo. In this study, we found that intravenous injection of either wild-type recombinant HCII or a variant with low affinity for HS (K173H) corrected the abnormally short thrombosis time of HCII-deficient mice, while a variant with low affinity for DS (R189H) had no effect. When HCII was incubated with frozen sections of the mouse carotid artery, it bound specifically to DS in the adventitia. HCII was undetectable in the wall of the uninjured carotid artery, but it became concentrated in the adventitia following endothelial injury. These results support the hypothesis that HCII interacts with DS in the vessel wall after disruption of the endothelium and that this interaction regulates thrombus formation in vivo.
He
Li
L
Division of Hematology, Washington University Medical School, 660 South Euclid Ave, St Louis, MO 63110, USA.
Giri
Tusar K
TK
Vicente
Cristina P
CP
Tollefsen
Douglas M
DM
D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D002808:Chondroitin Lyases / Q000378:metabolism; D003871:Dermatan Sulfate / Q000378:metabolism*; D005260:Female; D005343:Fibrinolytic Agents / Q000378:metabolism*; D015844:Heparin Cofactor II / Q000172:deficiency / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D008027:Light; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000494:pharmacology; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D013379:Substrate Specificity / Q000187:drug effects / Q000528:radiation effects; D013552:Swine; D013917:Thrombin / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000473:pathology; D013997:Time Factors
D002808:Chondroitin Lyases; D003871:Dermatan Sulfate; D005343:Fibrinolytic Agents; D015844:Heparin Cofactor II; D006497:Heparan Sulfate; D050505:Mutant Proteins; D011994:Recombinant Proteins; D013917:Thrombin