Heme Oxygenase-1 Expression in the Ovary Dictates a Proper Oocyte Ovulation, Fertilization, and Corpora Lutea Maintenance Maria L. Zenclussen 1, *, Federico Jensen 1, *, Sofia Rebelo 2 , Tarek El-Mousleh 1 , Pablo A. Casalis 3 , Ana C. Zenclussen 1 1 Department of Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany; 2 Instituto Gulbenkian de Cie ˆ ncia, Oeiras, Portugal 3 Department of Neurosurgery, Berlin Universitðtsmedizin, Berlin, Germany Introduction Female gonads are highly organized tissue struc- tures consisting of germ cells (oocytes) and somatic cells (granulose cells, theca cells, and stromal cells) whose interaction dictates the formation of the ovarian follicles as well as their development throughout different phases (primordial follicles, primary follicles, secondary follicles, and ovulatory follicles). Once the mature follicle (ovulatory follicle) is established, it may be either ovulated or die by mechanisms involving apoptosis. 1 After ovulation, the remaining follicle undergoes trans- formations that give rise to a transient endocrine structure named corpus luteum (CL), which is required for the establishment and maintenance of pregnancy in mammals. 1 Heme oxygenases (HO) catalyze the first and rate- limiting step in heme catabolism toward biliverdin, carbon monoxide (CO), and free iron. 2 The stress- responsive heme oxygenase-1 (HO-1) isoform, encoded by the Hmox1 gene, is cytoprotective 3 and modulates inflammation 4–6 preventing tissue injury. 7 In addition to its cytoprotective effect, HO-1 has been proposed to participate in the physiology of the ovary as it influences estereidogenesis. 8 Further, HO- 1 was implied in the release of gonadotropins from the pituitary gland. 9 Keywords fertilzation and corpus luteum, heme oxygenase-1, ovulation Correspondence Ana C. Zenclussen Department of Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany. E-mail: ana.zenclussen@med.ovgu.de *Both authors contributed equally to the paper. Submitted November 1, 2011; accepted November 4, 2011. Citation Zenclussen ML, Jensen F, Rebelo S, El-Mousleh T, Casalis PA, Zenclussen AC. Heme oxygenase-1 expression in the ovary dictates a proper oocyte ovulation, fertilization, and corpora lutea maintenance. Am J Reprod Immunol 2012; 67: 376–382 doi:10.1111/j.1600-0897.2011.01096.x Problem Animals deficient in Heme oxygenase-1 (HO-1, Hmox1 ) / ) mice) have impaired pregnancies, characterized by intrauterine fetal death. HO-1 expression has been shown to be essential for pregnancy by dictating placentation and intrauterine fetal development. Its absence leads to intrauterine fetal growth restriction and fetal loss, which is independent of the immune system. Defect in previous steps, e.g., ovulation, may, however, also count for their poor reproductive outcome. Method of study Here, we investigated ovulation after hormonal hyperstimulation in Hmox1 wild-type and knockout animals. Results and Conclusions We observed that animals lacking HO-1 produced significantly less oo- cytes after hormonal stimulation than wild type animals and this was mirrored by the number of corpora lutea in the ovary. Furthermore, ovulated oocytes from Hmox1 ) / ) animals were poorly fertilized com- pared with those from wild-type animals. In conclusion, we demonstrate here that HO-1 plays a pivotal role in the process of oocyte ovulation as well as fertilization, bringing to light a new and unsuspected role for HO-1. ORIGINAL ARTICLE American Journal of Reproductive Immunology 67 (2012) 376–382 376 ª 2011 John Wiley & Sons A/S