FTY720, a sphingosine analog, altered placentome histoarchitecture in ewes

The lysosphingolipid, sphingosine-1-phosphate, is a well-described and potent pro-angiogenic factor. Receptors, as well as the sphingosine phosphorylating enzyme sphingosine kinase 1, are expressed in the placentomes of sheep and the decidua of rodents; however, a function for this signaling pathway during pregnancy has not been established. The objective of this study was to investigate whether sphingosine-1-phosphate promoted angiogenesis within the placentomes of pregnant ewes. Ewes were given daily jugular injections of FTY720 (2-amino-2[2-(- 4-octylphenyl)ethyl]propate-1,3-diol hydrochloride), an S1P analog.

FTY720 infusion from days 30 to 60 of pregnancy did not alter maternal organ weights nor total number or mass of placentomes, but did alter placentome histoarchitecture. Interdigitation of caruncular crypts and cotyledonary villi was decreased, as was the relative area of cotyledonary tissue within placentomes. Also, the percentage of area occupied by cotyledonary villi per unit of placentome was increased, while the thickness of the caruncular capsule was decreased in ewes treated with FTY720. Further, FTY720 infusion decreased the number and density of blood vessels within caruncular tissue near the placentome capsule where the crypts emerge from the capsule. Finally, FTY720 infusion decreased asparagine and glutamine in amniotic fluid and methionine in allantoic fluid, and decreased the crown rump length of day 60 fetuses.

While members of the sphingosine-1-phosphate signaling pathway have been characterized within the uteri and placentae of sheep and mice, the present study uses FTY720 to address the influence of S1P signaling on placental development. We present evidence that modulation of the S1P signaling pathway results in the alteration of caruncular vasculature, placentome architecture, abundance of amino acids in allantoic and amniotic fluids, and fetal growth during pregnancy in sheep. The marked morphological changes in placentome histoarchitecture, including alteration in the vasculature, may be relevant to fetal growth and survival. It is somewhat surprising that fetal length was reduced as early as day 60, because fetal growth in sheep is greatest after day 60. The subtle changes observed in the fetuses of ewes exposed to FTY720 may indicate an adaptive response of the fetuses to cope with altered placental morphology.