Endothelins bind two major receptor subtypes, both of which belong to the seven- transmembrane G-coupled receptor superfamily . The two receptor subtypes were termed ETA (for aorta) and ETB (for bronchus). The ETA receptor has a high specificity for ET-1 (ET-1 >ET-2>ET3). The binding of endothelins to its receptors activates several transmembrane signalling pathways which most likely contribute to the diversity of the biological responses induced by this peptide.
General function
Receptor
Comment
Effect of Intraluteal Injection of Endothelin Type A Receptor Antagonist on PGF(2alpha)-induced Luteolysis in the Cow. Watanabe S et al. Endothelin-1 (ET-1) is a luteolytic mediator in the bovine corpus luteum (CL), and its action appears to be via endothelin type A receptor (ETR-A). Thus, the aim of the present study was to determine the effect of ETR-A antagonist on PGF(2alpha)-induced luteolysis in the cow. Cows on days 10-12 of the estrous cycle were subjected to five intraluteal injections of the ETR-A antagonist LU 135252 in saline or only saline at -0.5, 2, 4, 6, and 8 h after PGF(2alpha) administration (=0 h). Serial luteal biopsies were conducted to determine the expression of mRNA in the luteal tissue. There were no significant differences in the decrease in plasma progesterone (P) concentrations and the mRNA expressions of steroidogenic acute regulatory protein and 3 beta-hydroxysteroid dehydrogenase/Delta5, Delta4-isomerase between the ETR-A antagonist-treated group and the control group. However, the start of the decline in CL volume and blood flow area surrounding the CL was delayed for almost two days in the ETR-A antagonist-treated group compared to the control group. The mRNA expression of preproET-1 and endothelin type B receptor increased in both groups, while the ETR-A mRNA remained unchanged. In addition, caspase-3 mRNA expression increased significantly at 24 h in the control group only and its level was higher than that of the ETR-A antagonist-treated group. Thus, the present study suggests that ET-1 regulates structural luteolysis via ETR-A by controlling blood vessel contraction in the CL of the cow.
Paracrine regulation of the resumption of oocyte meiosis by endothelin-1. Kawamura K et al. Mammalian oocytes remain dormant in the diplotene stage of prophase I until the resumption of meiosis characterized by germinal vesicle breakdown (GVBD) following the preovulatory gonadotropin stimulation. Based on genome-wide analysis of peri-ovulatory DNA microarray to identify paracrine hormone-receptor pairs, we found increases in ovarian transcripts for endothelin-1 and endothelin receptor type A (EDNRA) in response to the preovulatory luteinizing hormone (LH)/human chorionic gonadotropin (hCG) stimulation. Immunohistochemical analyses demonstrated localization of EDNRA in granulosa and cumulus cells. In cultured preovulatory follicles, treatment with endothelin-1 promoted oocyte GVBD. The stimulatory effect of endothelin-1 was blocked by cotreatment with antagonists for the type A, but not related type B, receptor. The stimulatory effect of hCG on GVBD was partially blocked by the same antagonist. The endothelin-1 promotion of GVBD was found to be mediated by the MAPK/ERK pathway but not by the inhibitory G protein. Studies using cumulus-oocyte complexes and denuded oocytes demonstrated that the endothelin-1 actions are mediated by cumulus cells. Furthermore, intrabursal administration with endothelin-1 induced oocyte GVBD in preovulatory follicles. Our findings demonstrate a paracrine role of endothelin-1 in the induction of the resumption of meiosis and provide further understanding on the molecular mechanisms underlying the nuclear maturation of oocytes induced by the preovulatory LH surge.
ETA receptor mRNA levels are present in follicular cells of several species (Kamada et al., 1993, Iwai et al. 1996,Flores et al., 1996) as well as in the corpus luteum (Girsh et al., 1996, Apa et al., 1998). In bovine, high ETA receptor expression was found during luteal regression. ETA receptor is expressed by all three major cell populations of the bovine CL; steroidogenic small and large luteal cells, as well as in luteal endothelial cells. Among these various cell populations, the highest ETA receptor mRNA levels were found in endothelial cells (Mamluk et al., 1999).
Intrauterine infusion of BQ-610, an endothelin type A receptor antagonist, delays luteolysis in dairy heifers. Keator CS et al. Three separate in vivo experiments were conducted to evaluate the putative role of endothelin-1 (ET-1) during luteal regression in heifers. In Experiment 1, a single intraluteal injection of 500mug BQ-610 [(N,N-hexamethylene) carbamoyl-Leu-d-Trp (CHO)-d-Trp], a highly specific endothelin A (ET(A)) receptor antagonist, did not diminish the decline in plasma progesterone following a single exogenous injection of 25mg prostaglandin F2 alpha (PGF(2alpha)) administered at midcycle of the estrous cycle. In Experiment 2, six intrauterine infusions of 500mug BQ-610 given every 12h on days 16-18 delayed spontaneous luteolysis, as evidenced by an extended elevation (P=0.054) of plasma progesterone concentration. In Experiment 3, heifers were administered six intrauterine infusions of BQ-610 or saline on days 16-19, and peripheral blood samples were collected from day 11 to 16 (before infusion), hourly on days 16-19 (during infusion), and on days 20-25 (after infusion). BQ-610 treated heifers had markedly higher (P<0.0001) levels of plasma progesterone compared with saline controls, and this effect was most notable during the infusion period (treatment by period interaction; P/=0.05) between treatments. These results indicate that the in vivo antagonism of the ET(A) receptor can delay functional luteolysis, and supports the theory that ET-1 regulates luteal function in ruminants.
Expression regulated by
FSH, LH, Growth Factors/ cytokines
Comment
cAMP and IGF-I markedly decreased ETA receptor mRNA levels in granulosa and luteal cells.
Otani H,et al reported the presence and localization of endothelin receptor in the rat ovary and its regulation by pituitary gonadotropins.
In the present study we examined the regulation of receptors for endothelin 1 (ET-1) in rat granulosa cells. We examined the localization and regulation of ET receptors in immature rat ovary and the effects of ET-1 on steroidogenesis in cultured rat granulosa cells. The ovaries used in autoradiography were derived from pregnant mare serum gonadotropin and human chorionic gonadotropin-treated immature rats. Granulosa cells were obtained from diethylstilbestrol-treated immature rats and incubated with 125I-ET-1. Granulosa cells were cultured with ET-1 in the presence or absence of ovine follicle-stimulating hormone. The concentrations of sex steroid hormones in conditioned media were measured by radioimmunoassay. The binding site for ET-1 was localized in the granulosa cells, but not in thecal and luteal cells. Follicle-stimulating hormone (FSH) induced a dose-dependent increase in specific binding for ET-1 to cultured rat granulosa cells. In contrast, luteinizing hormone (LH) induced a dose-dependent decrease in specific binding for ET-1 to cultured rat granulosa cells. Conversely, treatment with prolactin and several sex steroid hormones had no effects on the specific binding of ET-1. Treatment with ET-1 inhibited FSH-stimulated accumulation of progesterone and estradiol in cultured rat granulosa cells. The results indicate that both FSH and LH influence the expression of ET-1 receptor, and that ET-1 may play a regulatory role in the ontogeny of the granulosa cell.
Gentili M, et al 2001 reported distinct expression of endothelin receptor subtypes A and B in
luteinized human granulosa cells.
Endothelins (ET) are potent vasoconstrictive peptides originally isolated from
vascular endothelial cells. Their biological effects are mediated through two
different receptors, the endothelin-1 (ET-1)-selective endothelin receptor
subtype ETA and the non-selective receptor subtype ETB. ET-1 protein has been
found in human ovarian follicular fluid and ET-1 mRNA expression has been
demonstrated in ovarian tissue. By means of RT-PCR and immunocytochemistry
the authors investigated whether luteinized human granulosa cells express ETA and ETB
receptors. Specific amplification products of ETA transcripts were detected in
all samples investigated. In contrast, only after using a three-fold amount of
ETB reverse transcripts it was possible to demonstrate specific, but weak
amplification products. In addition, immunocytochemical staining for ETA but
not for ETB was found in granulosa cell preparations.
Follicle stages
Preovulatory, Corpus luteum
Comment
Role of the Endothelin-1 System in the Luteolytic Process of Pseudopregnant Rabbits
Boiti C, et al .
The aim of this study was to better understand the role of the endothelin-1 (ET-1) system in the process controlling the corpora lutea (CL) life span in rabbits. ET-1 (10 microg iv) administration at days 9 and 12 of pseudopregnancy induced a functional luteolysis within 24 h of injection, but it was ineffective at both days 4 and 6. Pre-treatments with Bosentan, a dual ETA/ETB receptor antagonist, or cyclooxygenase (COX) inhibitor blocked the luteolytic action of ET-1, but not that induced by prostaglandin (PG) F2alpha. In CL cultured in vitro, ET-1 increased (P