[109] Ariane De Agostini Group (Gynaecology)

Anticoagulant heparan sulfates in female reproduction.

New functions for anticoagulant heparan sulfates in female reproduction : study of  the mechanism involved in ovulation and in placentation

Major tissue remodeling occurs in hormone-responsive tissues of the female genital tract, at ovulation and during gestation, involving proteolysis and tightly controlled inflammation. Disorders of tissue remodeling events are associated with female infertility in women with ovarian dysfunction and with gestational pathologies as pre-eclampsia.

Like heparin, anticoagulant heparan sulfate proteoglycans (aHSPG) bind and activate the coagulation inhibitor antithrombin III (AT). aHSPG are present in the vasculature and in the genital tract. The role of aHSPG in reproduction is demonstrated by the reduced fertility of mice harbouring an inactivated gene of 3-O-sulfotransferase, a key synthetic enzyme of aHSPG. These aHSPG deficient mice display multiple reproductive phenotypes, in the female ovulation is defective and gestation is hampered by inflammation around the placenta.

Beyond their anticoagulant activity in the vascular bed, aHSPG seem to play novel and unsuspected functions in the reproductive system. Ovulation and placenta development during gestation require extensive tissue remodeling. aHSPG seem to be involved in the control of the limited inflammation associated to this remodeling and the aim or our current research is to establish the mechanism of aHSPG action and to determine which inflammation mediators are involved in this process (AT, cytokines). We use in vivo transgenic mice models as well as cell culture models (murine and human ovarian, uterine and trophoblastic cells). These models are manipulated by hormones and inflammation mediators to reveal the action mechanism of aHSPG.

Recognition of the importance of aHSPG in reproductive physiology should allow to better understand the pathologies linked to the control of hemostasis and inflammation in the context of tissue remodeling during ovulation and gestation.