A novel pathway involving progesterone receptor, endothelin-2, and endothelin receptor B controls ovulation in mice

Gopinath S. Palanisamy, Yong Pil Cheon, Jaeyeon Kim, Athilakshmi Kannan, Quanxi Li, Marcey Sato, Srinivasa R. Mantena, Regine L. Sitruk-Ware, Milan K. Bagchi, Indrani C. Bagchi

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)2784-2795
Number of pages12
JournalMolecular Endocrinology
Issue number11
StatePublished - Nov 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Fingerprint Dive into the research topics of 'A novel pathway involving progesterone receptor, endothelin-2, and endothelin receptor B controls ovulation in mice'. Together they form a unique fingerprint.

Cite this