Semaphorin 3E-Plexin-D1 pathway regulates ovulation, granulosa cell luteinization, and ovarian angiogenesis in mice

Ovulation is induced by the luteinizing hormone surge and accompanied by granulosa cell luteinization and ovarian angiogenesis. Sema3E-Plexin-D1 pathway regulates angiogenesis in other tissues, but its role in the ovary was unknown. We report herein that the expression of Sema3E and its receptor, Plexin-D1, is dynamically regulated in the mouse ovary downstream of the LH surge. This regulation is mediated by CCAAT/enhancer-binding proteins α and β through modulating chromatin accessibility. Intraovarian injection of recombinant Sema3E results in reduced ovulation, impaired corpus luteum formation, and aberrant ovarian angiogenesis. These in vivo physiological abnormalities are consistent with altered expression of genes regulating these processes, and with data from in vitro cultured granulosa cells and/or ovarian stromal tissues treated with Sema3E or Plexin-D1 neutralizing antibody. Our findings shed light on the important role of Sema3E-Plexin-D1 pathway in the ovary, pinpointing it as a potential therapeutic target for fertility and infertility management. To explore the functional impact of evaluated Sema3E in the mouse ovary, we performed intraovarian injection of mouse recombinant Sema3E or IgG before hCG stimulation during standard superovulation. We then isolated ovarian granulosa cells and ovarian stromal tissue at 8 h post-hCG from ovaries injected with IgG vs Sema3E and performed bulk RNA-sequencing analysis.