title: Cyclic AMP-elevating Agents Promote Cumulus Cell Survival and Hyaluronan Matrix Stability, Thereby Prolonging the Time of Mouse Oocyte Fertilizability.
abstract: Cumulus cells sustain the development and fertilization of the mammalian oocyte. These cells are retained around the oocyte by a hyaluronan-rich extracellular matrix synthesized before ovulation, a process called cumulus cell-oocyte complex (COC) expansion. Hyaluronan release and dispersion of the cumulus cells progressively occur after ovulation, paralleling the decline of oocyte fertilization. We show here that, in mice, postovulatory changes of matrix are temporally correlated to cumulus cell death. Cumulus cell apoptosis and matrix disassembly also occurred in ovulated COCs cultured in vitro. COCs expanded in vitro with FSH or EGF underwent the same changes, whereas those expanded with 8-bromo-adenosine-3',5'-cyclic monophosphate (8-Br-cAMP) maintained integrity for a longer time. It is noteworthy that 8-Br-cAMP treatment was also effective on ovulated COCs cultured in vitro, prolonging the vitality of the cumulus cells and the stability of the matrix from a few hours to >2 days. Stimulation of endogenous adenylate cyclase with forskolin or inhibition of phosphodiesterase with rolipram produced similar effects. The treatment with selective cAMP analogues suggests that the effects of cAMP elevation are exerted through an EPAC-independent, PKA type II-dependent signaling pathway, probably acting at the post-transcriptional level. Finally, overnight culture of ovulated COCs with 8-Br-cAMP significantly counteracted the decrease of fertilization rate, doubling the number of fertilized oocytes compared with control conditions. In conclusion, these studies suggest that cAMP-elevating agents prevent cumulus cell senescence and allow them to continue to exert beneficial effects on oocyte and sperm, thereby extending in vitro the time frame of oocyte fertilizability.
authors.affiliation: From the Department of Biomedicine and Prevention, Section of Histology and Embryology, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Di Giacomo
authors.affiliation: From the Department of Biomedicine and Prevention, Section of Histology and Embryology, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Camaioni
authors.affiliation: From the Department of Biomedicine and Prevention, Section of Histology and Embryology, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Francesca G
authors.initials: FG
authors.lastname: Klinger
authors.affiliation: From the Department of Biomedicine and Prevention, Section of Histology and Embryology, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Bonfiglio
authors.affiliation: From the Department of Biomedicine and Prevention, Section of Histology and Embryology, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy salustri@med.uniroma2.it.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Salustri
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054885:Cumulus Cells / Q000166:cytology / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005306:Fertilization / Q000187:drug effects*; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D006820:Hyaluronic Acid / Q000378:metabolism*; D051379:Mice; D009865:Oocytes / Q000166:cytology / Q000378:metabolism*; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004815:Epidermal Growth Factor; D005640:Follicle Stimulating Hormone; D006820:Hyaluronic Acid; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D020889:Rolipram
keywords: apoptosis; cumulus cells; cyclic AMP (cAMP); extracellular matrix; fertilization; hyaluronan