Ovulation is stimulated by the preovulatory surge of the pituitary luteinizing hormone (LH). Because the ovulatory response is commonly identified with inflammation, we explored the involvement of reactive oxygen species (ROS) in this process. Our experiments show that administration of broad-range scavengers of oxidative species into the ovarian bursa of mice, hormonally induced to ovulate, significantly reduced the rate of ovulation. LH-induced cumulus mucification/expansion, a necessary requirement for ovulation, was prevented by antioxidants both in vivo and in an ex vivo system of isolated intact ovarian follicles. Along this line, H 2 O 2 fully mimicked the effect of LH, bringing about an extensive mucification/expansion of the follicle-enclosed cumulusoocyte complexes. Impaired progesterone production was observed in isolated follicles incubated with LH in the presence of the antioxidant agents. Furthermore, LH-stimulated up-regulation of genes, the expression of which is crucial for ovulation, was substantially attenuated upon ROS ablation. This system was also used for demonstrating the role of ROS in phosphorylation and activation of the EGF receptor as well as its downstream effector, p42/44 MAPK. Together, our results provide evidence that ovarian production of ROS is an essential preovulatory signaling event, most probably transiently triggered by LH.ovary | cumulus expansion O vulation is an essential prelude for successful reproduction. The ovulatory process is initiated by the midcycle surge of the pituitary luteinizing hormone (LH) that induces substantial biochemical, molecular, and cellular changes, culminating in the release of a mature ovum surrounded by the cumulus cells (1). Before ovulation, the cumulus cells produce an extracellular, hyaluronan-rich matrix that brings about cumulus mucification and its expansion. This response to LH that is essential for ovulation (2) is subsequent to the expression of a set of specific genes (3) such as prostaglandin synthase 2 (Ptgs2) (4), hyaluronan synthase 2 (Has2) (5), tumor necrosis-stimulated gene 6 (Tnfaip6) (6), and CCAAT/enhancer-binding protein β (Cebpb), a downstream target of p42/44 MAPK (Erk1/2) (7). Also essential for ovulation is LH-induced progesterone receptor (Pgr) expression as well as progesterone production (8).Numerous genes related to inflammation are induced in preovulatory follicles by the LH surge (9-12). Moreover, ovulation is suppressed by agents that inhibit acute inflammatory reactions (13). The analogy of ovulation with an acute inflammation (9, 14) may suggest a role for reactive oxygen species (ROS) along this process. ROS originate from inflammatory cells, such as macrophages and neutrophils, which are massively recruited after the LH surge to the ovary (15), and their depletion impairs ovulation (16, 17). Cyclooxygenase 2 (Ptgs2), the expression of which is a hallmark for LHinduced ovulation, is associated with inflammation and generates ROS (18). ROS are also byproducts of monooxygenase reactions mediated by the P450...

Ovulation and inflammation share common attributes, including immune cell invasion into the ovary. The present study aims at deciphering the role of dendritic cells (DCs) in ovulation and corpus luteum formation. Using a CD11c-EYFP transgenic mouse model, ovarian transplantation experiments, and fluorescence-activated cell sorting analyses, we demonstrate that CD11c-positive, F4/80-negative cells, representing DCs, are recruited to the ovary under gonadotropin regulation. By conditional ablation of these cells in CD11c-DTR transgenic mice, we revealed that they are essential for expansion of the cumulus-oocyte complex, release of the ovum from the ovarian follicle, formation of a functional corpus luteum, and enhanced lymphangiogenesis. These experiments were complemented by allogeneic DC transplantation after conditional ablation of CD11c-positive cells that rescued ovulation. The pro-ovulatory effects of these cells were mediated by up-regulation of ovulation-essential genes. Interestingly, we detected a remarkable anti-inflammatory capacity of ovarian DCs, which seemingly serves to restrict the ovulatory-associated inflammation. In addition to discovering the role of DCs in ovulation, this study implies the extended capabilities of these cells, beyond their classic immunologic role, which is relevant also to other biological systems.

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