Gonadotropin-releasing hormone increases the release of extracellular vesicles from gonadotropes

Abstract

While extracellular vesicles play a role in intercellular communication, it is not known how their release is regulated. We show here that hypothalamic gonadotropin-releasing hormone (GnRH) stimulates extracellular vesicle (EV) formation associated with annexin A5 (ANXA5) from pituitary gonadotropes. The results show that 1) membrane blebs containing ANXA5 are produced after GnRH agonist (GnRHa) stimulation of gonadotropes and that this is observed in situ as a loss of distinction at cell-cell boundaries, 2) EV containing ANXA5 are increased by GnRHa, 3) a gonadotrope-derived EV fraction stimulates LH release from other gonadotropes, and 4) an increase in ANXA5-loaded EV occurs in the plasma of ovariectomized rats. Finally, we also showed that 5) GnRHa stimulation of blebbing and EV-ANXA5 were suppressed by a protein kinase A inhibitor. These present results demonstrate a novel autocrine/paracrine mechanism mediated through the production of EV containing ANXA5. A hormonal regulation mechanism of cell-cell communication by means of EV is suggested.