Cyclooxygenase-2-derived prostaglandin E(2) directs oocyte maturation by differentially influencing multiple signaling pathways.
ABSTRACT The process of oocyte maturation, which impacts ovulation and fertilization, is complex and requires an integration of the endocrine, paracrine, juxtacrine, and autocrine signaling pathways. This process involves an intimate interaction between the oocyte and encircling cumulus cells within a follicle, a unique venue for somatic and germ cell communication. Cumulus cell expansion and resumption of meiosis with germinal vesicle breakdown are major events in oocyte maturation. Cyclooxygenase-2 (COX-2)-derived prostaglandin E(2) (PGE(2)) is a known critical mediator of oocyte maturation, but the diverse function of this lipid mediator in oocyte maturation, ovulation, and fertilization has not been fully appreciated. We show here that gonadotropins in coordination with PGE(2) signaling via its cell surface G-protein-coupled EP2 and EP4 receptor subtypes direct cumulus cell expansion and survival and oocyte meiotic maturation by differentially impacting cAMP-dependent protein kinase, MAPK, NF-kappaB, and phosphatidylinositol 3-kinase/Akt pathways. This study is unique in the sense that it provides evidence for new site- and event-specific involvement of these signaling pathways under the influence of COX-2-derived PGE(2) during the critical stages of this somatic-germ cell interaction, an absolute requirement for oocyte maturation.
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ABSTRACT: Prostaglandin E2 (PGE2) is a key mediator of ovulation. All four PGE2 [EP] receptors are expressed in the primate follicle, but the specific role of each EP receptor in ovulatory events is poorly understood. To examine the ovulatory events mediated via these EP receptors, preovulatory monkey follicles were injected with vehicle, the PG synthesis inhibitor indomethacin, or indomethacin+PGE2. An ovulatory dose of human chorionic gonadotropin (hCG) was administered; the injected ovary was collected 48 hours later and serially sectioned. Vehicle-injected follicles showed normal ovulatory events, including follicle rupture, absence of an oocyte, and thickening of the granulosa cell layer. Indomethacin-injected follicles did not rupture and contained oocytes surrounded by unexpanded cumulus; granulosa cell hypertrophy did not occur. Follicles injected with indomethacin+PGE2 were similar to vehicle-injected ovaries, indicating that PGE2 restored the ovulatory changes inhibited by indomethacin. Additional follicles were injected with indomethacin+an agonist for each EP receptor. EP1, EP2, and EP4 agonists each promoted aspects of follicle rupture, but no single EP agonist recapitulated normal follicle rupture as seen in follicles injected with either vehicle or indomethacin+PGE2. While EP4 agonist-injected follicles contained oocytes in unexpanded cumulus, the absence of oocytes in EP1 agonist- and EP2 agonist-injected follicles suggests that these EP receptors promote cumulus expansion. Surprisingly, the EP3 agonist did not stimulate any of these ovulatory changes, despite the high level of EP3 receptor expression in the monkey follicle. Therefore, agonists and antagonists selective for EP1 and EP2 receptors hold the most promise for control of ovulatory events in women.Endocrinology 02/2014; · 4.72 Impact Factor
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ABSTRACT: Despite several decades since the birth of the first test tube baby and the first calf derived from an in vitro-fertilised embryo, the efficiency of assisted reproductive technologies remains less than ideal. Poor oocyte competence is a major factor limiting the efficiency of in vitro embryo production. Developmental competence obtained during oocyte growth and maturation establishes the foundation for successful fertilisation and preimplantation embryonic development. Regulation of molecular and cellular events during fertilisation and embryo development is mediated, in part, by oocyte-derived factors acquired during oocyte growth and maturation and programmed by factors of follicular somatic cell origin. The available evidence supports an important intrinsic role for oocyte-derived follistatin and JY-1 proteins in mediating embryo developmental progression after fertilisation, and suggests that the paracrine and autocrine actions of oocyte-derived growth differentiation factor 9, bone morphogenetic protein 15 and follicular somatic cell-derived members of the fibroblast growth factor family impact oocyte competence and subsequent embryo developmental progression after fertilisation. An increased understanding of the molecular mechanisms mediating oocyte competence and stage-specific developmental events during early embryogenesis is crucial for further improvements in assisted reproductive technologies.Reproduction Fertility and Development 12/2013; 26(1):37-47. · 2.58 Impact Factor
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ABSTRACT: The purpose of this study was to evaluate the effect of omega-3 α-linolenic acid (ALA) added to the IVM medium on embryo development of prepubertal sheep oocytes. Experiment 1 investigated the effect of ALA at different concentrations (0 [control], 50, 100, and 200 μM) and DMSO (100 μM) in IVM media on cumulus cell expansion and oocyte nuclear maturation and on synthesis of prostaglandins (PGE2 and PGF2α). Experiment 2 investigated the effects of ALA at different concentrations in the IVM medium on oocyte fertilization, cleavage, and developmental potential to blastocyst stage and changes in estradiol and progesterone concentrations in the spent IVM media. IVM oocytes were fertilized with frozen-thawed spermatozoa capacitated in a serum-free sperm medium. Presumptive zygotes were cultured 8 days in synthetic oviductal fluid (SOF) medium without serum. Blastocyst quality was assessed by counting total cell number and the number of apoptotic cells using Hoechst and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Nuclear maturation of oocytes and the number of fully expanded cumulus cells were reduced after treatment with 200 μM of ALA compared with other groups (P ≤ 0.05). Supplementation with ALA increased both PGE2 and PGF2α concentrations in the spent media (P ≤ 0.05). No differences were observed in blastocyst development among control (12.2%) and 50, 100, and 200 μM ALA groups (6.9%, 11.5% and 14.0%, respectively). However, the total cell number (46.50 ± 5.85, 67.94 ± 6.71, 45.20 ± 6.37, and 59.80 ± 5.51, respectively; P ≤ 0.05) and apoptotic cell number (6.45 ± 0.89, 2.48 ± 0.81, 4.02 ± 1.15, and 3.67 ± 1.15, respectively; P ≤ 0.05) were significantly improved. After IVM, estradiol concentration was lower and progesterone concentration was higher in ALA groups compared with the control group (P ≤ 0.05). In conclusion, these results revealed that ALA affects prepubertal sheep embryo quality associated with alteration of releasing reproductive hormones.Theriogenology 06/2014; · 2.08 Impact Factor