An unexpected role for anticoagulant heparan sulfate proteoglycans in reproduction.

Abstract

Major tissue remodelling occurs in hormone responsive tissues of the female genital tract, at ovulation and during gestation, involving proteolysis and inflammation. Disorders of tissue remodelling events are associated with infertility in women with luteinized unruptured follicle syndrome and with gestational pathologies as preeclampsia. Ovulation impairment is an important factor of infertility and a major concern in reproductive medicine. The gonadotrophin discharge inducing ovulation triggers proteolytic activities involved in the breakdown of the follicular wall and elicits an acute inflammatory reaction in the ovary. Tight control of these reactions is required to allow successful ovulation while avoiding excessive tissue damage. Anticoagulant heparan sulfate proteoglycans (aHSPG), like heparin, possess a pentasaccharide sequence which binds and activates antithrombin III. These proteoglycans are produced by endothelial cells and are thought to endow the vascular wall with antithrombotic properties. aHSPG are also present in the reproductive tract; in the ovary they are strongly expressed in granulosa cells of preovulatory follicles and they are co-localised with serine protease inhibitors involved in the control of proteolytic activities at ovulation. The presence of aHSPG in the oviduct, in the uterus and in human follicular fluid, suggests that they could play additional distal roles in gestation. The females exhibited impaired ovarian function as well as intrauterine growth restriction linked to delayed placenta development. In these mice, the placenta is challenged by inflammation at mid-gestation, occasionally resulting in miscarriage and maternal death. Collectively, these observations suggest that aHSPG are involved in the control of inflammatory events occurring during tissue remodelling in hormone-responsive tissues. Further studies are needed to identify the inflammation mediators involved in this process.