Mice deficient in heparan sulfate 3-O-sulfotransferase-1: normal hemostasis with unexpected perinatal phenotypes

Heparan sulfate that contains antithrombin binding sites is designated as anticoagulant heparan sulfate (HS^act) since, in vitro, it dramatically enhances the neutralization of coagulation proteases by antithrombin. Endothelial cell production of HS^act is controlled by the Hs3st1 gene, which encodes the rate limiting enzyme—heparan sulfate 3-O-sulfotransferase-1 (Hs3st1). It has long been proposed that levels of endothelial HS^act may tightly regulate hemostatic tone. This potential in vivo role of HS^act was assessed by generating Hs3st1^–/– knockout mice. Hs3st1^–/– and Hs3st1^+/+ mice were evaluated with a variety of methods, capable of detecting altered hemostatic tone. However, both genotypes were indistinguishable. Instead, Hs3st1^–/– mice exhibited lethality on a specific genetic background and also showed intrauterine growth retardation. Neither phenotypes result from a gross coagulopathy. So although this enzyme produces the majority of tissue HS^act, Hs3st1^–/– mice do not show an obvious procoagulant phenotype. These results suggest that the bulk of HS^act is not essential for normal hemostasis and that hemostatic tone is not tightly regulated by total levels of HS^act. Moreover, the unanticipated non-thrombotic phenotypes suggest structure(s) derived from this enzyme might serve additional/alternative biologic roles. Published in 2003.