title: A novel pathway involving progesterone receptor, endothelin-2, and endothelin receptor B controls ovulation in mice.
abstract: The steroid hormone progesterone (P) plays a pivotal role during ovulation. Mice lacking P receptor (Pgr) gene fail to ovulate due to a defect in follicular rupture. The P receptor (PGR)-regulated pathways that modulate ovulation, however, remain poorly understood. To identify these pathways, we performed gene expression profiling using ovaries from mice subjected to gonadotropin-induced superovulation in the presence and in the absence of CDB-2914, a synthetic PGR antagonist. Prominent among the genes that were down-regulated in response to CDB-2914 was endothelin (ET)-2, a potent vasoactive molecule. ET-2 mRNA was transiently induced in mural granulosa cells of the preovulatory follicles immediately preceding ovulation. This induction was absent in the ovaries of PGR null mice, indicating a critical role of this receptor in ET-2 expression. To investigate the functional role of ET-2 during ovulation, we employed selective antagonists of endothelin receptors, ETR-A and ETR-B. Mice treated with an ETR-B antagonist exhibited a dramatic (>85%) decline in the number of released oocytes. Strong expression of ETR-B was observed in the mural and cumulus granulosa cells of the preovulatory follicles as well as in the capillaries lining the inner border of the theca interna. We also identified cGMP-dependent protein kinase II, a previously reported PGR-regulated gene, as a downstream target of ET-2 during ovulation. Collectively, our studies uncovered a unique pathway in which ET-2, produced by PGR in mural granulosa cells, acts in a paracrine or autocrine manner on multiple cell types within the preovulatory follicle to control the final events leading to its rupture.
authors.affiliation: Department of Veterinary Biosciences, University of Illinois at Urbana-Champaign, Urbana, Illinois 61802, USA.
authors.forename: Gopinath S
authors.initials: GS
authors.lastname: Palanisamy
authors.forename: Yong-Pil
authors.initials: YP
authors.lastname: Cheon
authors.forename: Jaeyeon
authors.initials: J
authors.lastname: Kim
authors.forename: Athilakshmi
authors.initials: A
authors.lastname: Kannan
authors.forename: Quanxi
authors.initials: Q
authors.lastname: Li
authors.forename: Marcey
authors.initials: M
authors.lastname: Sato
authors.forename: Srinivasa R
authors.initials: SR
authors.lastname: Mantena
authors.forename: Regine L
authors.initials: RL
authors.lastname: Sitruk-Ware
authors.forename: Milan K
authors.initials: MK
authors.lastname: Bagchi
authors.forename: Indrani C
authors.initials: IC
authors.lastname: Bagchi
mesh_terms: D000818:Animals; D065131:Endothelin B Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019333:Endothelin-2 / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006107:Granulosa Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009649:Norpregnadienes / Q000008:administration & dosage; D006080:Ovarian Follicle / Q000378:metabolism; D010053:Ovary / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010060:Ovulation / Q000187:drug effects / Q000502:physiology*; D011372:Progestins / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism / Q000502:physiology*; D017466:Receptors, Endothelin / Q000378:metabolism / Q000502:physiology*; D011980:Receptors, Progesterone / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D065131:Endothelin B Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019333:Endothelin-2; D009649:Norpregnadienes; D011372:Progestins; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D011980:Receptors, Progesterone; C094854:ulipristal