Angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7) and Mas receptor in gonadal and reproductive functions

Abstract Angiotensin (Ang)-(1-7) is an active peptide formed from Ang I or Ang-(1-9) by multiple proteolytic steps involving angiotensin-converting enzyme (ACE) 1 and other peptidases, or by a single cleavage of Ang II catalyzed chiefly by ACE2. The effects of Ang-(1-7) are mediated by the G protein-coupled receptor Mas (or Mas1), encoded by the protooncogene MAS. The reproductive system expresses ACE2 quite abundantly and therefore is able to generate Ang-(1-7) using precursor peptides produced locally or taken from circulation. In several mammalian species, Ang-(1-7) stimulates ovarian follicle growth, oocyte maturation and ovulation. The peptide is found in human endometrium, mostly during the secretory phase of menstrual cycle when the uterus is receptive to embryo implantation. Rat models and human observational studies suggest that Ang-(1-7) is part of the maternal adaptive response to pregnancy and its deficiency is associated with poor circulation in the placental bed. Knockout mice revealed a relevant participation of Mas-mediated stimulus to the maintenance of normal spermatogenesis, even though the animal can still reproduce without it. In addition, the vasorelaxant effect of Ang-(1-7) participates in the physiological mechanism of corpus cavernosum blood influx and penile erection. We conclude that preclinical evidence encourages the pursuit of treatments for female and male reproductive dysfunctions based on Mas agonists, starting with its natural ligand Ang-(1-7).