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Coordinate Expression of Anticoagulant Heparan Sulfate Proteoglycans and Serine Protease Inhibitors in the Rat Ovary: A Potent System of Proteolysis Control¹

^a Infertility Clinic, Department of Gynaecology and Obstetrics, Geneva University Hospital, 1211 Geneva 14, Switzerland ^b Fondation pour Recherches Médicales, University of Geneva, 1205 Geneva, Switzerland

During the reproductive cycle, ovarian follicles undergo major tissue-remodeling involving vascular changes and proteolysis. Anticoagulant heparan sulfate proteoglycans (aHSPGs) are expressed by granulosa cells during the development of the ovarian follicle. The function of aHSPGs in the ovary is unknown, but they might be involved in proteolysis control through binding and activation of serine protease inhibitors. To identify functional interactions between aHSPGs and heparin-binding protease inhibitors in the follicle, we have coordinately localized aHSPGs, antithrombin III, protease nexin-1, and plasminogen activator inhibitor-1 in the rat ovary during natural and gonadotropin-stimulated cycles. Anticoagulant HSPGs were visualized by autoradiography of cryosections incubated with ¹²⁵I-antithrombin III, and protease inhibitors were assessed by immunohistochemistry and Northern blot hybridization. Anticoagulant HSPGs were expressed in follicles before ovulation, were transiently decreased in postovulatory follicles, and were abundant in the corpus luteum, mainly on capillaries. Anticoagulant HSPGs were colocalized with protease nexin-1 in follicles from the early antral stage until ovulation, with antithrombin III in the preovulatory stage and after ovulation, and with plasminogen activator inhibitor-1 in the corpus luteum. These data demonstrate that aHSPGs are critically expressed in the ovary to interact sequentially with protease nexin-1, antithrombin III, and plasminogen activator inhibitor-1 during the cycle. The specificity of these inhibitors is shifted toward thrombin inhibition in the presence of heparin, suggesting that aHSPGs direct their action to control fibrin deposition in the follicle. The occupation of aHSPGs antithrombin-binding sites by mutant R393C antithrombin III, injected in the ovarian bursa, decreased ovulation efficiency, further supporting the involvement of aHSPGs in the ovulation process.

First decision: 9 January 2001.

¹ This work was supported by Swiss National Fund for Scientific Research grants 32-39587.93 and 32-49646.96. S.H. was the recipient of a Swiss Federal Fellowship. M.P. was supported in part by fellowships from the Sir Jules Thorn Trust and from the Fondation pour Recherches Médicales, Geneva.

² Correspondence: Ariane de Agostini, Fondation pour Recherches Médicales, 64 avenue de la Roseraie, 1205 Geneva, Switzerland. FAX: 41 22 347 59 79; ariane.deagostini{at}medecine.unige.ch

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