Inter-relationships between endothelin and prostaglandin F2alpha in corpus luteum function

In cattle and other species, the corpus luteum plays a central role in the regulation of cyclicity and maintenance of pregnancy. In the absence of fertilization and implantation, the corpus luteum undergoes functional and morphological regression or luteolysis. Luteal regression is initiated in domestic ruminants by surges of prostaglandin F2alpha (PGF2alpha) from the uterus. Despite intensive investigation, the mechanisms by which PGF2alpha causes luteal regression remain undetermined. Recent studies from several laboratories have demonstrated that endothelial cells and their product, endothelin 1, are required for the manifestation of the luteolytic effects of PGF2alpha. Experimental evidence strongly supports the concept that luteal endothelin 1 inhibits luteal steroidogenesis and mediates the effects of PGF2alpha. Endothelin 1 caused a dose-dependent reduction in both basal and luteinizing hormone-stimulated biosynthesis of progesterone and prostacyclin, and an increase in PGF2alpha by ovine and bovine luteal cells. Specific receptors for endothelin 1 were identified on large and small bovine luteal cells, and the addition of specific endothelin receptor antagonists abolished the inhibitory effects of endothelin 1. Luteal endothelin 1 content increased as the cyclic corpus luteum aged, and the highest concentrations were observed during luteolysis. The amount of mRNA encoding endothelin 1 was greatly increased during the period of luteolysis. Gene expression for endothelin 1 was increased, in a time-dependent manner, in corpora lutea collected from heifers and ewes after exogenous administration of PGF2alpha. In heifers, exogenous PGF2alpha resulted in increased luteal output of endothelin 1. In ewes, the luteolytic effects of PGF2alpha were mitigated by pretreatment with a specific endothelin receptor antagonist. Administration of endothelin 1 or a sub-luteolytic dose of PGF2alpha to ewes reduced concentrations of jugular venous progesterone but did not shorten luteal lifespan. However, a combination of endothelin 1 and PGF2alpha acted synergistically to bring about complete luteolysis and reduced lifespan of the corpus luteum. In summary, endothelin 1 appears to have a direct effect on luteal cells in cattle and sheep, and it plays an essential role in mediating the luteolytic effects of PGF2alpha.