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.
Shworak
Nicholas W
NW
Section of Cardiology, Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire 03755, USA. nicholas.shworak@dartmouth.edu
HajMohammadi
Sassan
S
de Agostini
Ariane I
AI
Rosenberg
Robert D
RD
D000818:Animals; D000831:Animals, Newborn; D000925:Anticoagulants / Q000378:metabolism; D001665:Binding Sites; D001777:Blood Coagulation / Q000235:genetics / Q000502:physiology; D002240:Carbohydrate Sequence; D006487:Hemostasis / Q000235:genetics / Q000502:physiology*; D006497:Heparan Sulfate / Q000737:chemistry / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010641:Phenotype; D015238:Sulfotransferases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
D000925:Anticoagulants; D006497:Heparan Sulfate; D015238:Sulfotransferases; C102180:heparan sulfate D-glucosaminyl 3-O-sulfotransferase