FTY720,a sphingosine analog,altered placentome histoarchitecture in ewes

Background: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.Results: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.Conclusions: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.

Supplementing N-carbamoylglutamate in late gestation increases newborn calf weight by enhanced placental expression of mTOR and angiogenesis factor genes in dairy cows

The objective of this study was to investigate whether supplementation with N-carbamoylglutamate(NCG)to cows during late gestation alters uteroplacental tissue nutrient transporters,calf metabolism and newborn weight.Thirty multiparous Chinese Holstein cows were used in a randomized complete block design experiment.During the last 28 d of pregnancy,cows were fed a diet without(CON)or with NCG(20 g/d per cow).The body weight of calves was weighed immediately after birth.Placentome samples were collected at parturition and used to assess mRNA expression of genes involved in transport of arginine,glucose,fatty acid and angiogenesis factors,as well as the mammalian target of rapamycin(mTOR)pathway.Blood samples of calves before colostrum consumption were also collected for the detection of plasma parameters,amino acids(AA)and metabolomics analysis.The newborn weight(P=0.02)and plasma Arg concentration of NCG-calves was significantly higher(P=0.05)than that of CON-calves,and the plasma concentrations of urea nitrogen tended to be lower(P=0.10)in the NCG group.The mRNA abundance of genes involved in glucose transport(solute carrier family 2 member 3[SLC2 A3],P<0.01),angiogenesis(nitric oxide synthase 3[NOS3],P=0.02),and mTOR pathway(serine/threonine-protein kinase 1[ACT1],P=0.10;euka ryotic translation initiation factor 4 B pseudogene 1[EIF4 BP1],P=0.08;EIF4 EBP2,P=0.04;and E74-like factor 2[ELF2],P=0.03)was upregulated in the placentome of NCG-supplemented cows.In addition,17 metabolites were significantly different in the placentome of NCG-supplemented cows compared to non-supplemented cows,and these metabolites are mainly involved in arginine and proline metabolism,alanine,aspartate and glutamate metabolism,and citrate cycle.In summary,the increased body weight of newborn calves from the NCG supplemented dairy cows maybe attributed to the increased angiogenesis and uteroplacental nutrient transport and to the activated mTOR signal pathway,which may result in the increased nutrient supply to the fetus,and improved AA metabolism and urea cycle of the fetus.