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Identification, Characterization, and Biological Activity of Endothelin Receptors in Human Ovary¹

Department of Clinical Physiopathology, Andrology Unit (M.M., R.M., G.Fo.) and Endocrinology Unit (A.P.), Department of Human Anatomy and Histology (T.B., G.B.V.), Department of Pharmacology (S.A., S.F.), Department of Obstetrics and Gynecology (T.S.), University of Florence, 50139 Florence; and the First Department of Internal Medicine, Division of Andrology, University of Catania (A.C., N.B.), Catania 95123, Italy

Address all correspondence and requests for reprints to: Mario Maggi, M.D., Andrology Unit, Viale Pieraccini 6, 50139 Florence, Italy.

We previously reported the expression of endothelin-1 (ET-1) in granulosa cells (GCs) of the human ovary and the presence of ET-1-like immunoreactivity in human follicular fluid obtained from women in an in vitro fertilization program. In follicular fluid, but not in plasma, the levels of ET-1-like immunoreactivity were higher in gonadotropin-stimulated vs. spontaneous cycles, suggesting hormonal regulation of follicular ET-1. To identify and characterize ET receptors in human ovary, we performed autoradiography, radioligand binding, and functional studies. Mathematical analysis of families of self- and cross-competition curves among [¹²⁵I]ET-1, [¹²⁵I]ET-3, and selective analogs indicates that human ovary expresses both subtypes of ET receptors, i.e. ET_A and ET_B receptors. However, the concentration of the ET_B site was 100-fold lower than that of the ET_A one. By using [¹²⁵I]ET-1, we demonstrated that the density of binding sites in human ovary is not affected by the hormonal milieu (similar concentrations in normal cycling, postmenopausal, and combined oral contraceptive-treated women). In situ binding studies indicate that the majority of ET_A and ET_B receptors are expressed in the blood vessels of the ovary. In particular, ET_A receptors are abundant in the ovulatory follicles and localized in the theca interna, in close proximity to the granulosa layer. Few GCs of the ovulatory follicle were specifically labeled. Conversely, in the rat ovary, used as a control, ET_B receptors were predominantly expressed and localized in GCs. Accordingly, ET_B receptors negatively regulated estrogen accumulation in rat GCs. In human granulosa-luteal cells, neither ET-1 (unselective ligand) nor ET-3 or sarafotoxin 6c (ET_B ligands) affected estrogen or progesterone secretion. ET-1 was 2.5-fold more potent than noradrenaline in eliciting contraction of ovarian artery, acting through the ET_A receptor. Our results indicate that in human ovary, at variance with rat ovary, the endothelin system is primarily involved in the regulation of ovarian blood flow and not steroidogenesis.

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