Abstract
The objective was to elucidate gene expression differences in uterus, caruncle, and cotyledon of ewes with subclinical pregnancy toxemia (SCPT) and healthy ewes, and to identify associated biological functions and pathways involved in pregnancy toxemia. On Day 136 (±1 day) post-breeding, ewes (n = 18) had body condition score (BCS; 1–5; 1, emaciated; 5, obese) assessed, and blood samples were collected for plasma glucose and β-hydroxybutyrate (BHBA) analyses. The ewes were euthanized, and tissue samples were collected from the gravid uterus and placentomes. Based on BCS (2.0 ± 0.02), glucose (2.4 ± 0.33), and BHBA (0.97 ± 0.06) concentrations, ewes (n = 10) were grouped as healthy (n = 5) and subclinical SCPT (n = 5) ewes. The mRNA expressions were determined by quantitative PCR method, and prediction of miRNA partners and target genes for the predicted miRNA were identified using miRDB (http://mirdb.org/miRDB/). Top ranked target genes were used to identify associated biological functions and pathways in response to SPCT using PANTHER. The angiogenesis genes VEGF and PlGF, and AdipoQ, AdipoR2, PPARG, LEP, IGF1, IGF2, IL1b, and TNFα mRNA expressions were lower in abundances, whereas hypoxia genes eNOS, HIF1a, and HIF 2a, and sFlt1 and KDR mRNA expressions were greater in abundances in uterus and placenta of SCPT ewes compared to healthy ewes (P < 0.05). The predicted miRNA and associated target genes contributed to several biological processes, including apoptosis, biological adhesion, biological regulation, cellular component biogenesis, cellular process, developmental process, immune system process, localization, metabolic process, multicellular organismal process, reproduction, and response to stimulus. The target genes were involved in several pathways including angiogenesis, cytoskeletal regulation, hypoxia response via HIF activation, interleukin signaling, ubiquitin proteasome, and VEGF signaling pathway. In conclusion, genes associated with blood vessel remodeling were lower in abundances and that the genes associated with hypoxic conditions were greater in abundances in the uteroplacental compartment of SCPT ewes. It is obvious that the factors that influence placental vascular development and angiogenesis as noted in this study set the course for hemodynamic changes and hence have a major impact on the rate of transplacental nutrient exchange, fetal growth, and health of the dam.
Highlights
Pregnancy toxemia is a metabolic disorder of pregnant ewes, caused by an abnormal metabolism of carbohydrates and fats, which occurs during the final stage of pregnancy
The VEGF, PlGF, AdipoQ, AdipoR2, PPARG, Lep, IGF1, IGF2, IL1b, and TNFα mRNA expressions were lower in abundance in cotyledon, caruncle, and uterus of subclinical pregnancy toxemia (SCPT) ewes compared to healthy ewes (Figure 1; P < 0.05)
The sFlt1, KDR, eNOS, HIF1a, and HIF2a mRNA expressions were greater in abundance in cotyledon, caruncle, and uterus of SCPT ewes compared to healthy ewes (P < 0.05)
Summary
Pregnancy toxemia is a metabolic disorder of pregnant ewes, caused by an abnormal metabolism of carbohydrates and fats, which occurs during the final stage of pregnancy. Glucose is the principal carbon source for placental and fetal oxidative metabolism and tissue formation [5, 6]. A total of 30–50% of maternal glucose production in late gestation is taken up by uterine and fetal tissues [5–8], and 50–70% of this amount is used by the uteroplacental unit [6, 9, 10]. During late gestation, increased energy demands of the rapidly developing fetus(es) cause an unbalanced lipid and carbohydrate metabolism in the pregnant animal and putting them at risk to pregnancy toxemia [1, 2]. The impaired fat and carbohydrate metabolism produces increased levels of fatty acids and ketone bodies, mainly β-hydroxybutyrate (BHBA), besides the decreased glucose concentration [3, 4]
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