Neurotensin drives theca cell migration during ovulation in primates†

Theca cells are a critical steroidogenic cell type of the ovarian follicle and corpus luteum. The ovulatory luteinizing hormone (LH) surge (or human chorionic gonadotropin (hCG)) stimulates theca cell relocation from the stroma surrounding the dominant follicle to full integration into the developing corpus luteum. Luteinizing hormone/human chorionic gonadotropin also stimulates granulosa cells to produce local mediators of ovulation, including the peptide neurotensin (NTS). To determine if hCG-stimulated NTS regulates theca cell relocation within the ovulatory follicle, vehicle or an NTS receptor antagonist was injected into a macaque dominant follicle, and ovaries were removed 48 h after hCG administration. Additional ovaries with dominant follicles were collected without administration of hCG (pre-hCG). Theca cells were sparse in the ovarian stroma surrounding pre-hCG follicles, while theca cells were abundant in the stroma and granulosa cell layer of recently-ovulated, hCG-treated follicles. Intrafollicular injection of a general NTS receptor antagonist or antagonist selective for a specific NTS receptor (NTSR1 or SORT1) reduced theca migration into the granulosa cell layer after hCG. In vitro, NTS stimulated macaque theca cell migration in conventional and 3-dimensional migration assays, and NTS receptor antagonists blocked NTS-stimulated migration. Neurotensin-stimulated theca cell migration in vitro was influenced by ovarian extracellular matrix components, with laminin reducing theca cell migration. NTS also increased theca cell number in vivo and stimulated theca cell proliferation in vitro. In summary, hCG-stimulated NTS acts directly at theca cells via NTSR1 and SORT1 to stimulate theca cell migration during ovulation and transformation of the ovulatory follicle into the corpus luteum.