Prostaglandin dehydrogenase is a target for successful induction of cervical ripening.

Abstract

The cervix represents a formidable structural barrier for successful induction of labor. Approximately 10% of pregnancies undergo induction of cervical ripening and labor with prostaglandin (PG) E₂ or PGE analogs, often requiring many hours of hospitalization and monitoring. On the other hand, preterm cervical ripening in the second trimester predicts preterm birth. The regulatory mechanisms of this paradoxical function of the cervix are unknown. Here, we show that PGE₂ uses cell-specific EP2 receptor-mediated increases in Ca²⁺ to dephosphorylate and translocate histone deacetylase 4 (HDAC4) to the nucleus for repression of 15-hydroxy prostaglandin dehydrogenase (15-PGDH). The crucial role of 15-PGDH in cervical ripening was confirmed in vivo. Although PGE₂ or 15-PGDH inhibitor alone did not alter gestational length, treatment with 15-PGDH inhibitor + PGE₂ or metabolism-resistant dimethyl-PGE₂ resulted in preterm cervical ripening and delivery in mice. The ability of PGE₂ to selectively autoamplify its own synthesis in stromal cells by signaling transcriptional repression of <i>15-PGDH</i> elucidates long sought-after molecular mechanisms that govern PG action in the cervix. This report details unique mechanisms of action in the cervix and serves as a catalyst for (<i>i</i>) the use of 15-PGDH inhibitors to initiate or amplify low-dose PGE₂-mediated cervical ripening or (<i>ii</i>) EP2 receptor antagonists, HDAC4 inhibitors, and 15-PGDH activators to prevent preterm cervical ripening and preterm birth.