Abstract
BackgroundTocopherols have biphasic, proangiogenic and antiangiogenic therapeutic effects. The objective of this clinical trial was to clarify tocopherol's placental angiogenic potential in late pregnant ewes following oral supplementation.MethodsEighteen pregnant ewes during late gestation were selected for this study. Ewes were given oral supplementation of 500 mg of alpha-tocopherol (aT; N = 6) or 1000 mg of gamma-tocopherol (gT; N = 7) or placebo (CON; N = 5) once daily from 107 to 137 days post breeding. Serum was obtained at weekly intervals and tissue samples were obtained at the end of supplementation to: 1) evaluate tocopherol concentrations in serum, uterus and placentome; 2) evaluate relative mRNA expressions of Vascular Endothelial Growth Factor (VEGF), Placental Growth Factor (PlGF), endothelial Nitric Oxide Synthase (eNOS) and Hypoxia Inducible Factors (HIF) in uterus, caruncle and cotyledon; 3) analyze the morphometry of the placental vascular network.ResultsSupplementation of aT or gT resulted in increased concentrations in serum, placentome and uterus compared to control (P < 0.05). In aT group, mRNA expressions of PlGF, eNOS and HIF-1α in cotyledon were greater than the CON group. In gT group, mRNA expressions of VEGF, eNOS, HIF-1 alpha and HIF-2 alpha in caruncle and uterus, and HIF-1α in cotyledon, were greater than the CON group. Morphometry analysis revealed increased angiogenesis in the supplemented groups.ConclusionDaily oral supplementation of aT or gT increased angiogenesis in the placental vascular network in pregnant ewes during late gestation. Increase in placental angiogenesis may provide nutrients required for the development and growth of fetus during late pregnancy.
Highlights
Tocopherols have biphasic, proangiogenic and antiangiogenic therapeutic effects
The findings of this study indicated that oral supplementation of tocopherols to pregnant ewes during late gestation increased their serum concentrations; increased their concentrations in uterine and placentomal tissue; alpha tocopherol increased mRNA expression of placental growth factors (PlGF), endothelial Nitric Oxide Synthase (eNOS) and Hypoxia inducible factor (HIF)-1a in cotyledon compared to placebo; gamma tocopherol increased Vascular Endothelial Growth Factor (VEGF) and eNOS mRNA expressions in caruncle and uterus, and HIF-1a in cotyledon, HIF-1a and HIF-2 a in caruncle and uterus compared to placebo; morphometry analysis of angiogenic parameters favored increased angiogenesis
This study evaluated cellular responses to supplementation in order to understand the mechanisms behind the biological effects of tocopherols on placental angiogenesis during late gestation in pregnant ewes
Summary
Tocopherols have biphasic, proangiogenic and antiangiogenic therapeutic effects. The objective of this clinical trial was to clarify tocopherol’s placental angiogenic potential in late pregnant ewes following oral supplementation. Tissue hypoxia is the main driving force for angiogenesis, a growing body of evidence has demonstrated that oxidative stress can be a potent trigger for the development of new vessels [3,4,5,6]. Human and animal studies have demonstrated that chronic supplementations with tocopherols have biphasic, proangiogenic and antiangiogenic therapeutic effects [18,19,20,21,22]. A recent study concluded that tocoretinols not tocopherols suppressed Vascular Endothelial Growth Factor (VEGF) induced angiogenesis [23]
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