Endothelial anticoagulant heparan sulfate mediates anti‐inflammatory effects of antithrombin

Anticoagulant heparan sulfate (HS AT+ ) is thought to catalyze antithrombin's (AT) anticoagulant activity; however, HS AT+ deficient mice ( Hs3st1 −/− ) show normal hemostasis. Perhaps endothelial HS AT+ mediates anti‐inflammatory effects of AT. We examined leukocyte‐endothelial interactions (LEIs) by intravital microscopy of cremaster muscle venules. Human AT, or vehicle, was given 2 h before exteriorization of the cremaster muscle, an intrascrotal injection of TNFα, or an intraperitoneal injection of lipopolysaccharide (LPS). In Hs3st1 +/+ mice, AT reduced select LEIs induced by cremaster exteriorization and LPS, but enhanced TNFα induced LEIs. LPS treated Hs3st1 −/− , vs. Hs3st1 +/+ , mice trended towards enhanced mortality (P=0.17) and select LEIs were enhanced (P<0.01). Most importantly, AT treatment produced opposite effects on LPS induced leukocyte adhesion efficiency; Hs3st1 +/+ mice exhibited a 7‐fold reduction (P<0.001) but Hs3st1 −/− mice had a 3.7‐fold elevation (P<0.02). In Hs3st1 −/− mice, HS AT+ levels were normal on leukocytes but undetectable on cremaster endothelial cells. We conclude that AT's inhibition of LEIs is context dependent, likely involving a balance of pro‐ and anti‐inflammatory activities. Endothelial HS AT+ mediates AT anti‐inflammatory activity. Supported in part by Bayer‐CIHR‐CBS‐HQ Partnership Fund to PLG; NIH R01 HL079104 , and AHA GIA 0250613N to NWS.