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J. Biol. Chem., Vol. 283, Issue 42, 28115-28124, October 17, 2008

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Human Follicular Fluid Heparan Sulfate Contains Abundant 3-O-Sulfated Chains with Anticoagulant Activity^*

Ariane I. de Agostini¹, Ji-Cui Dong, Corinne de Vantéry Arrighi, Marie-Andrée Ramus, Isabelle Dentand-Quadri, Sébastien Thalmann, Patricia Ventura, Victoria Ibecheole, Felicia Monge^¶||, Anne-Marie Fischer^¶||, Sassan HajMohammadi^**, Nicholas W. Shworak^**, Lijuan Zhang, Zhenqing Zhang, and Robert J. Linhardt

From the Department of Gynaecology and Obstetrics, Geneva University Hospitals and University of Geneva, Geneva 14, Switzerland, Université Paris Descartes, Faculté of Médecine, Paris, F-75014, France, ^¶INSERM Unité 765, Paris, F-75006, France, ^||Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpital Européen Georges Pompidou, Paris, F-75015, France, ^**Section of Cardiology, Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire 03756, the Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, and the Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180

Anticoagulant heparan sulfate proteoglycans bind and activate antithrombin by virtue of a specific 3-O-sulfated pentasaccharide. They not only occur in the vascular wall but also in extravascular tissues, such as the ovary, where their functions remain unknown. The rupture of the ovarian follicle at ovulation is one of the most striking examples of tissue remodeling in adult mammals. It involves tightly controlled inflammation, proteolysis, and fibrin deposition. We hypothesized that ovarian heparan sulfates may modulate these processes through interactions with effector proteins. Our previous work has shown that anticoagulant heparan sulfates are synthesized by rodent ovarian granulosa cells, and we now have set out to characterize heparan sulfates from human follicular fluid. Here we report the first anticoagulant heparan sulfate purified from a natural human extravascular source. Heparan sulfate chains were fractionated according to their affinity for antithrombin, and their structure was analyzed by ¹H NMR and MS/MS. We find that human follicular fluid is a rich source of anticoagulant heparan sulfate, comprising 50.4% of total heparan sulfate. These antithrombin-binding chains contain more than 6% 3-O-sulfated glucosamine residues, convey an anticoagulant activity of 2.5 IU/ml to human follicular fluid, and have an anti-Factor Xa specific activity of 167 IU/mg. The heparan sulfate chains that do not bind antithrombin surprisingly exhibit an extremely high content in 3-O-sulfated glucosamine residues, which suggest that they may exhibit biological activities through interactions with other proteins.

Received for publication, July 14, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grant GM38060 (to R. J. L.). This work was also supported by Swiss National Foundation Grant 3200B0-102148/1 (to A. d. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2 and Tables 1–3.

¹ To whom correspondence should be addressed: Fondation pour Recherches Médicales, 1205 Genève, Switzerland. Fax: 41-22-347-5979; E-mail: Ariane.Deagostini{at}medecine.unige.ch.

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