Tocopherol induced angiogenesis in placental vascular network in late pregnant ewes.
BACKGROUND
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.


METHODS
Eighteen 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.


RESULTS
Supplementation 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-1alpha 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-1alpha in cotyledon, were greater than the CON group. Morphometry analysis revealed increased angiogenesis in the supplemented groups.


CONCLUSIONS
Daily 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.
Kasimanickam
Ramanathan K
RK
College of Veterinary Medicine, Washington State University, Pullman, WA 99164, USA. ramkasi@vetmed.wsu.edu
Kasimanickam
Vanmathy R
VR
Rodriguez
Jacobo S
JS
Pelzer
Kevin D
KD
Sponenberg
Philip D
PD
Thatcher
Craig D
CD
D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005865:Gestational Age; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010920:Placenta / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D000072483:Placenta Growth Factor; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D011270:Pregnancy, Animal; D012756:Sheep; D024505:Tocopherols / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D051793:Hypoxia-Inducible Factor 1; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D052250:Nitric Oxide Synthase Type III; D024505:Tocopherols